EP0177478B2 - Libération prolongée de somatotropines biologiquement actifs - Google Patents
Libération prolongée de somatotropines biologiquement actifs Download PDFInfo
- Publication number
- EP0177478B2 EP0177478B2 EP85870135A EP85870135A EP0177478B2 EP 0177478 B2 EP0177478 B2 EP 0177478B2 EP 85870135 A EP85870135 A EP 85870135A EP 85870135 A EP85870135 A EP 85870135A EP 0177478 B2 EP0177478 B2 EP 0177478B2
- Authority
- EP
- European Patent Office
- Prior art keywords
- somatotropin
- composition
- oil
- animal
- previous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 230000002035 prolonged effect Effects 0.000 title claims description 32
- 239000003921 oil Substances 0.000 claims abstract description 99
- 235000019198 oils Nutrition 0.000 claims abstract description 99
- 229910052751 metal Inorganic materials 0.000 claims abstract description 61
- 239000002184 metal Substances 0.000 claims abstract description 61
- 239000011701 zinc Substances 0.000 claims abstract description 32
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 108010006025 bovine growth hormone Proteins 0.000 claims abstract description 31
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 31
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 11
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 7
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 7
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 6
- 239000008158 vegetable oil Substances 0.000 claims abstract description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 170
- 108010051696 Growth Hormone Proteins 0.000 claims description 160
- 102000018997 Growth Hormone Human genes 0.000 claims description 160
- 241001465754 Metazoa Species 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 239000002245 particle Substances 0.000 claims description 29
- 241000283690 Bos taurus Species 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 22
- 239000006185 dispersion Substances 0.000 claims description 17
- 239000008267 milk Substances 0.000 claims description 15
- 235000013336 milk Nutrition 0.000 claims description 14
- 210000004080 milk Anatomy 0.000 claims description 14
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 13
- 239000000194 fatty acid Substances 0.000 claims description 13
- 229930195729 fatty acid Natural products 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000004071 biological effect Effects 0.000 claims description 11
- 238000007911 parenteral administration Methods 0.000 claims description 10
- 239000008159 sesame oil Substances 0.000 claims description 9
- 235000011803 sesame oil Nutrition 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- 235000019483 Peanut oil Nutrition 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 7
- 230000002708 enhancing effect Effects 0.000 claims description 7
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- 239000011777 magnesium Substances 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 7
- 239000000312 peanut oil Substances 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- 241000283707 Capra Species 0.000 claims description 4
- 241001494479 Pecora Species 0.000 claims description 4
- 241000282898 Sus scrofa Species 0.000 claims description 4
- 239000005639 Lauric acid Substances 0.000 claims description 3
- 235000021314 Palmitic acid Nutrition 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 229910052793 cadmium Inorganic materials 0.000 claims description 3
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000002285 corn oil Substances 0.000 claims description 3
- 235000005687 corn oil Nutrition 0.000 claims description 3
- 235000012343 cottonseed oil Nutrition 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000004006 olive oil Substances 0.000 claims description 3
- 235000008390 olive oil Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052797 bismuth Inorganic materials 0.000 claims description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 239000003549 soybean oil Substances 0.000 claims description 2
- 235000012424 soybean oil Nutrition 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 235000019482 Palm oil Nutrition 0.000 claims 2
- 235000019484 Rapeseed oil Nutrition 0.000 claims 2
- 235000019485 Safflower oil Nutrition 0.000 claims 2
- 239000002385 cottonseed oil Substances 0.000 claims 2
- 239000002540 palm oil Substances 0.000 claims 2
- 235000005713 safflower oil Nutrition 0.000 claims 2
- 239000003813 safflower oil Substances 0.000 claims 2
- 159000000003 magnesium salts Chemical class 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 22
- 229920001184 polypeptide Polymers 0.000 abstract description 20
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 20
- 239000004411 aluminium Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 44
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 42
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 40
- 239000004202 carbamide Substances 0.000 description 21
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 235000017060 Arachis glabrata Nutrition 0.000 description 18
- 244000105624 Arachis hypogaea Species 0.000 description 18
- 235000010777 Arachis hypogaea Nutrition 0.000 description 18
- 235000018262 Arachis monticola Nutrition 0.000 description 18
- 235000020232 peanut Nutrition 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 241000207961 Sesamum Species 0.000 description 15
- 235000003434 Sesamum indicum Nutrition 0.000 description 15
- -1 Cl= Chemical class 0.000 description 13
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 13
- 238000011068 loading method Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000011592 zinc chloride Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 8
- 150000001450 anions Chemical class 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- PYMGGGYYAVKIJL-UHFFFAOYSA-K aluminum hexadecanoate dihydroxide Chemical compound [OH-].[OH-].[Al+3].CCCCCCCCCCCCCCCC([O-])=O PYMGGGYYAVKIJL-UHFFFAOYSA-K 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 150000002739 metals Chemical class 0.000 description 6
- 240000008042 Zea mays Species 0.000 description 5
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 5
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- RDIVANOKKPKCTO-UHFFFAOYSA-K aluminum;octadecanoate;hydroxide Chemical compound [OH-].[Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O RDIVANOKKPKCTO-UHFFFAOYSA-K 0.000 description 5
- 230000000975 bioactive effect Effects 0.000 description 5
- 235000005822 corn Nutrition 0.000 description 5
- 235000013365 dairy product Nutrition 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000002510 pyrogen Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 241001133760 Acoelorraphe Species 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 240000002791 Brassica napus Species 0.000 description 4
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 4
- 244000020518 Carthamus tinctorius Species 0.000 description 4
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 4
- 235000010469 Glycine max Nutrition 0.000 description 4
- 244000068988 Glycine max Species 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 240000007817 Olea europaea Species 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 229940083916 aluminum distearate Drugs 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000011026 diafiltration Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000003801 milling Methods 0.000 description 4
- 239000012053 oil suspension Substances 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 3
- 244000299507 Gossypium hirsutum Species 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 3
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical class [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000122 growth hormone Substances 0.000 description 3
- 239000012510 hollow fiber Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 229940070765 laurate Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 150000003751 zinc Chemical class 0.000 description 3
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 244000000231 Sesamum indicum Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229960004198 guanidine Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 230000004572 zinc-binding Effects 0.000 description 2
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- 239000004185 Penicillin G procaine Substances 0.000 description 1
- 102000003743 Relaxin Human genes 0.000 description 1
- 108090000103 Relaxin Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 238000010266 Sephadex chromatography Methods 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000473945 Theria <moth genus> Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229940024548 aluminum oxide Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000011082 depyrogenation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 150000002646 long chain fatty acid esters Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 150000000221 oxazepines Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019370 penicillin G procaine Nutrition 0.000 description 1
- 229940056362 penicillin g procaine Drugs 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 210000001764 somatotrope Anatomy 0.000 description 1
- 230000002628 somatotropin effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- MJIBOYFUEIDNPI-HBNMXAOGSA-L zinc 5-[2,3-dihydroxy-5-[(2R,3R,4S,5R,6S)-4,5,6-tris[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxy]-2-[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxymethyl]oxan-3-yl]oxycarbonylphenoxy]carbonyl-3-hydroxybenzene-1,2-diolate Chemical compound [Zn++].Oc1cc(cc(O)c1O)C(=O)Oc1cc(cc(O)c1O)C(=O)OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c([O-])c([O-])c2)c1 MJIBOYFUEIDNPI-HBNMXAOGSA-L 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- This invention relates to biologically active somatotropin compositions which can be parenterally administered for prolonged release in animals, to methods of using such compositions, to metal-associated somatotropins useful in certain of such compositions, and to processes for preparing such metal-associated somatotropins.
- biologically active polypeptides Although prolonged activity of some biologically active (bioactive) polypeptides can be achieved by parenterally administering only very small doses, others are required in sufficient serum concentrations and/or have such a short half-life in serum that a substantial dose (e.g. at least about 100 mg) must be administered to provide the desired biological effect over an extended time such as a week or longer.
- a substantial dose e.g. at least about 100 mg
- Somatotropins growth hormones
- polypeptides have been parenterally administered in liquid vehicles which may optionally contain hydration retardants (antihydration agents) or in association with metals or metal compounds that further lower their solubility in body fluids.
- hydration retardants antihydration agents
- substantial concentrations of the polypeptide in the vehicle would be advantageous.
- bioactive polypeptides are very viscous in substantial concentrations and consequently difficult to inject or otherwise administer in such concentrations.
- many commonly used antihydration agents add viscosity and can diminish convenient injectability of such compositions.
- each polypeptide is different, e.g. in its three-dimensional structure and its interaction with other substances, the feasibility of achieving a prolonged effective release with a high loading of polypeptide in a suitable vehicle is impossible to predict or demonstrate theoretically. Yet in many cases, such prolonged release compositions must be developed if the biological activity of the polypeptide is to be provided in a useful, economical fashion.
- Oil suspensions have been also utilized for certain low molecular weight (MW) therapeutic substances other than penicillin.
- MW low molecular weight
- Lachman et al. in U.S. Patent 3,676,557 discloses long-acting formulations of up to 50% pamoate salts of normorphinones in oil suspensions gelled with AlMS.
- Sieger et al in U.S. Patent 4,016,273 discloses prolonged-release formulations of up to 40% pamoate salts of oxazepines in oils gelled with aluminum stearates.
- Anschel in U.S. Patent 2,964,448 discloses suspensions of relaxin (about 2%) in a vegetable oil gelled with AlMS.
- Anschel indicates such a suspension provides relaxation comparable to that in oil without gelling agent (e.g. 5-7 days) and discloses a longer effect (up to 23 days) by heat treating the suspension containing AlMS.
- Geller in U.S. Patent 3,869,549 discloses injectable prolonged-release compositions containing "extremely small doses", e.g. "fractions of a milligram" of a peptide.
- growth hormones are mentioned, specific examples are of water soluble corticotrophin (ACTH) preparations active for 7-8 days.
- Geller discloses compositions containing acid addition salts of ACTH analogs suspended in groundnut oil gelled with aluminum distearate (AlDS) or adsorbed on AlDS subsequently dispersed in such oil. In either case the analog is in Geller's injectable formulations in concentrations of only 0.03-0.1% and weight ratios of peptide to the aluminum salt no greater than 0.5.
- compositions for extended release of analogs of LH-RH hormone are disclosed by Nestor et al. in U.S. Patent 4,256,737.
- Those compositions contain salts of the hormone, including polyvalent metal (e.g. zinc) salts, in vegetable oil gelled with aluminum salts of fatty acids.
- the LH-RH analogs are administered at concentrations of 0.01-1% in the injected composition.
- the present invention provides a substantially non-aqueous composition comprising a somatotropin, and, as a continuous phase of said composition, a biocompatible oil, characterised in that the composition is for parenteral administration and the amount of the somatotropin is at least 10% by weight of the composition.
- the invention further includes a method for achieving prolonged release of a biologically active somatotropin into the circulatory system of an animal, which comprises parenteral administration to said animal of a composition of the invention; and a method for enhancing lean-to-fat ratio, feed efficiency or milk production of an animal, which comprises parenteral administration to said animal of a composition of the invention.
- the invention provides a method for preparing a non-aqueous somatotropin composition, comprising dispersing finely-divided, discrete particles of the somatotropin in a biocompatible oil in proportions such that the oil forms a continuous phase of the resulting dispersion and said dispersion contains at least 10% by weight of said somatotropin, and under conditions such that the resulting dispersion is substantially non-aqueous and the somatotropin in the resulting dispersion has a particulate median volume diameter not greater than 15 micrometres, said dispersing being carried out at temperatures compatible with the biological activity of the somatotropin.
- substantially non-aqueous means essentially anhydrous or containing water in such low proportion that it does not intolerably accelerate release of the polypeptide in the animal. Although this proportion of water varies with each composition of the invention, it is most commonly less than about 2% (even more typically less than about 1%) in a form having such an effect on the polypeptide release.
- non-toxic refers herein to components of compositions of this invention that are reasonably safe and/or innocuous when used in appropriate amounts and under appropriate conditions in parenteral administration of such compositions.
- the somatotropin is administered in chemically uncombined form.
- a form e.g. chemically combined with another substance
- the somatotropin can be predominantly (e.g. fully) chemically associated with a non-toxic metal or in an ester, amide or other form(s) which provide the desired bioactivity and do not impart intolerable side effects.
- the metal can be present as the metal per se (e.g. in a metal salt of or complex with the somatotropin or in the form of a salt or complex of the metal with one or more other anions.
- monovalent metals e.g. sodium or potassium
- polyvalent metals are preferred for use in many other instances.
- examples of such polyvalent metals include zinc, iron, calcium, bismuth, barium, magnesium, manganese, aluminum, copper. cobalt, nickel or cadmium.
- metal-associated somatotropin are reaction products of such metals, e.g. in ionic form, with dissolved somatotropin.
- the ratio of metal to somatotropin may vary depending on the number of active sites of the somatotropin that associate with such metal during the formation process.
- the metal may be associated with some or all negatively-charged amino acid (e.g.
- the metal may be associated in a salt of the somatotropin , occluded within folds, crystals or amorphous shapes of the somatotropin, or associated as a cation bridge between at least two somatotropin molecules.
- Novel and preferred metal-associated somatotropin useful in this invention include somatotropins associated with zinc. In some instances, these may contain up to about 5% zinc or more, based on the weight of the somatotropin. To minimize the chance of undesirable injection site responses in the animals, however, it may be desirable for them to contain no more than about 2%, and in some instances no more than about 1% zinc (same basis). In many preferred embodiments these somatotropins associated with zinc contain at least about 0.3% (usually at least about 0.5%) zinc (same basis), although lower percentages of zinc may be suitable in some cases.
- somatotropin salts useful in this invention include (a) acid addition salts formed with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric or nitric; or organic acids, e.g. acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, ascorbic, benzoic, tannic, pamoic, alginic, polyglutamic, naphthalenesulfonic, naphthalene-disulfonic or polygalacturonic; (b) salts with polyvalent organic cations, e.g. N'-dibenzylethylenediamine or ethylenediamine; and (c) combinations of two or more of the aforementioned types of salts, e.g. zinc tannate.
- inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, phosphoric or nitric
- salts of zinc, iron, calcium, magnesium, manganese, sodium, potassium and mixtures thereof are those of zinc, sodium or potassium.
- Such salts when administered in a biocompatible oil in the proportions employed in compositions of this invention, interact with the oil resulting in a matrix or other structure that, surprisingly, enhances prolongation of the somatotropin release at effective levels.
- a biocompatible oil i.e., an oil having no intolerable adverse effect on the somatotropin, the animal, or, in the case of animals whose products enter the food chain, the consumers of such products.
- oils are of low acidity and essentially free from rancidity.
- oil means a fatty oil or fat that is liquid at the body temperature of the animal. Thus, such an oil will melt or at least begin to melt below about 40° and preferably below about 35°. Oils that are liquid at about 25° may facilitate injection or other administration of some compositions of this invention.
- polyunsaturated (e.g. partially hydrogenated) oils may be favored for greater biocompatibility with the animal or other reasons.
- the biocompatible oil is composed essentially of triglycerides, i.e., long chain (generally C 8 -C 24 , preferably C 12 -C 18 ) fatty acid esters of glycerol, or mixtures of triglycerides and such tatty acids (preferably in only minor proportions, e.g. less than about 10% free fatty acid).
- other trihydroxy or polyhydroxy compounds can be substituted for the glycerol.
- Especially preferred oils include vegetable oils such as olive, sesame seed, peanut, sunflower seed, soybean, cottonseed, corn, safflower, palm, rapeseed and mixtures of such oils. Sesame and peanut oils are highly preferred for many embodiments. Oils of animal or mineral origin or synthetic oils (including long chain fatty acid esters of glycerol or propylene glycol) can also be employed provided they are sufficiently biocompatible.
- such an oil constitutes a predominant part by weight of such compositions.
- the continuous phase of biocompatible oil has in most cases desirably finely divided, discrete particles of the somatotropin relatively uniformly dispersed therein, e.g. in a suspension.
- the upper limit of loading of the somatotropin is where the oil ceases to exist in a continuous phase because there is insufficient oil to fully envelop substantially all of the polypeptide in the composition.
- compositions of this invention contain a somatotropin at desirably high loading levels, for instance at least 10%. Even higher loadings of somatotropin, e.g. at least 15%, are often desirable and especially efficacious. Loadings of 20% or higher, e.g. at least 30% or even up to 42% or higher, can be used advantageously in parenterally injectable compositions comprising a somatotropin (e.g. bovine), in particular when the somatotropin is associated with a polyvalent metal such as zinc. Such compositions can provide prolonged release of the somatotropin (as measured in the blood stream of cattle or other animals) for periods of up to 30 days or longer.
- a somatotropin at desirably high loading levels, for instance at least 10%. Even higher loadings of somatotropin, e.g. at least 15%, are often desirable and especially efficacious. Loadings of 20% or higher, e.g. at least 30% or even up to 42% or higher, can
- Substantially non-aqueous compositions comprising loading levels of somatotropin or other as high as about 10% have not been suggested in any prior art of which I am aware. In such prior art oil preparations are restricted to very low loadings of polypeptides, i.e., no more than about 2%. (See U.S. Patents 2,964,448; 3,869,549; and 4,256,737.)
- compositions of this invention may also comprise, in addition to the biocompatible oil, an "antihydration agent" which term as used herein means a substance that retards hydration of a given composition of this invention, or the somatotropin and/or biocompatible oil therein, and thereby decreases and/or stabilizes the rate of release of the somatotropin from that composition following administration to an animal.
- an antihydration agent means a substance that retards hydration of a given composition of this invention, or the somatotropin and/or biocompatible oil therein, and thereby decreases and/or stabilizes the rate of release of the somatotropin from that composition following administration to an animal.
- an antihydration agent which term as used herein means a substance that retards hydration of a given composition of this invention, or the somatotropin and/or biocompatible oil therein, and thereby decreases and/or stabilizes the rate of release of the somatotropin from that composition following administration to an animal.
- Exemplary antihydration agents include various salts of organic acids, for instance fatty acids having from 8 (preferably at least 10) to 22 (preferably up to 20) carbon atoms, e.g. aluminum, zinc, magnesium or calcium salts of lauric acid, palmitic acid or stearic acid. Such salts may be mono-, di- or tri-substituted, depending on the valence of the metal and the degree of oxidation of the metal by the acid. Particularly useful are the aluminum salts of such fatty acids. Aluminum monostearate and distearate are particularly preferred antihydration agents. Others that are useful include aluminum tristearate, calcium mono- and distearate, magnesium mono- and distearate and the corresponding palmitates or laurates. In many embodiments, the concentration of such an antihydration agent, based on the weight of the oil plus that agent, will be advantageously between about 1% and about 10% (most typically between about 2% and about 5%), although other concentrations may be suitable in some cases.
- both the somatotropins and the antihydration agents tend to increase viscosity of the compositions of this invention.
- that ratio is generally at least I, more typically at least 3, even more typically at least 4, and most commonly at least 6.
- that ratio is generally not greater than 40 and more typically not greater than 20.
- compositions of this invention can be used for prolonged release of somatotropins in animals, for example with the object of enhancing lean-to-fat ratio, teed efficiency and milk production in various mammalian species including cattle (e.g., dairy cows), sheep, goats and swine.
- somatotropin means a polypeptide that has biological activity and chemical structure substantially similar to those of a somatotropin produced in the pituitary gland of an animal.
- somatotropins include natural somatotropins produced by pituitary somatotropic cells, and alternatively somatotropins expressed by genetically transformed microorganisms such as E. coli , other bacteria or yeasts.
- Such alternatively produced somatotropins may have an amino acid sequence identical to the natural somatotropin or may be analogs having one or more variations in amino acid sequence which may provide enhanced biological activity or some other advantage.
- somatotropins for which this invention is particularly useful include bovine and porcine somatotropins, e.g.
- somatotropins optionally have a methionine residue at the N-terminus, e.g. a methionine resulting from microbial translation of an ATG start signal in a gene for the somatotropin.
- methionine residues in the somatotropin are no more than about 20% (preferably no more than about 10%) formyl-methionine, to lessen any tendency of the animal's foreign body defenses to degrade the somatotropin.
- compositions of this invention indicate that a substantial amount of somatotropin is in some cases released initially upon injections. This is referred to as a "burst" which is believed to result from a surface area increase occasioned by injection or other administration. In some cases a modest burst may be desirable, e.g. to activate a desired biological effect.
- a characteristic useful in formulating compositions of this invention is the relationship of initial burst level determined by measuring the concentration of somatotropin in serum of the treated animal shortly after administration, to the prolonged release level determined by measuring the concentration of somatotropin tide in serum of the animal at a later time.
- the burst level is the concentration of the somatotropin in serum 24 hours after injection
- the prolonged release level is the concentration of the somatotropin in serum 14 days after injection.
- compositions of this invention Another useful characteristic in evaluating and formulating compositions of this invention is "syringeability", a measure of how well the composition flows through a hypodermic injection needle. If particles of the somatotropin are too large or the composition is too viscous, it may require an inordinate pressure to force the composition through such a needle.
- “syringeability” is determined by measuring the time for a volume of a composition of this invention to pass through an 18 gauge hypodermic needle having an I.D. of 0.033 inches (0.838 mm) and a length of 4 cm when a pressure of 173 psi (1193 kPa) is applied to the composition in a syringe fitted with the needle.
- “Syringeability” for compositions of this invention is desirably at least 0.03 milliliters per second (ml/sec). Preferably such syringeability is higher, e.g. at least about 0.1 ml/sec or, even more desirably, at least about 0.3 ml/sec.
- compositions of this invention can be prepared by adding somatotropin to oil alone or to oil having an antihydration agent suspended or dissolved in the oil. It is often convenient to dissolve an antihydration agent to provide a gelled oil.
- a gelling agent such as a fatty acid salt of aluminum can be added as a powder to a quantity of oil stirred to effect a suspension of that powder.
- the stirred suspension may be desirably heated to at least the melting point of the fatty acid salt (e.g. at least 155° for AlMS) at which point the salt will dissolve in the oil. Lower temperatures can be used if the gelling or other antihydration agent is adequately dissolved.
- Thorough and continuous stirring helps avoid agglomeration of the fatty acid salt and maintain the dispersion. Usually, the heating and stirring should continue until the suspended salt is fully dissolved. It is often desirable to maintain stirring for additional time to assure complete dissolution.
- the oil solution of fatty acid salt can then be cooled, e.g. to room temperature, where a fairly stable gel structure will result.
- the gel should be kept under vacuum or desiccant to avoid contamination with water which mad adversely affect the gel structure.
- the somatotropin can then be added to the oil at any temperature (e.g. room) that avoids intolerably adverse effects (e.g. denaturing).
- any temperature e.g. room
- bovine somatotropin has been added to such an oil at temperatures from about 4 to about 125° without adversely affecting biological activity.
- This addition of somatotropin is preferably carried out under vacuum to avoid contamination by water or air bubbles.
- Such addition is desirably carried out by slow addition of finely divided somatotropin to the oil undergoing high-shear mixing to provide uniform dispersion of the somatotropin particles.
- Size reduction of the somatotropin particles is often desirable and can be accomplished, e.g., by use of a ball mill in which a suspension of the somatotropin is mixed with a quantity of stainless steel balls having diameters of, e.g., 0.3-0.6 cm. This can be advantageously carried out simultaneously with such dispersion in the lower portion of a vessel in which high shear mixing is effected. This is particularly advantageous with highly charged somatotropins that are difficult to reduce in size to particles having a median particle diameter based on volume not greater than 15 micrometres (i.e., 50% of the volume of the particles having diameters not greater than 15 micrometres).
- Use of somatotropins of low particle size e.g.
- compositions of this invention have been found desirable for enhancing syringeability of compositions of this invention.
- somatotropin particles By operating such a ball mill the somatotropin particles can be conveniently reduced to such a preferred median particle diameter no greater than 5 micrometres. Thereafter, the composition of this invention can be recovered from the ball mill by filtration (advantageously under vacuum).
- compositions of this invention are attractively useful for parenteral administration, e.g. by injection intraperitoneally or, usually more desirably, subcutaneously or intramuscularly.
- the duration of prolonged release is that period of time during which the somatotropin is delivered at the rate required for the desired biological effect, typically indicated by the concentration of the somatotropin in the animal's circulating blood stream.
- the period of prolonged release is desirably at least about 7 days. In other cases, it may be at least about 15 days, or more desirably for many applications at least about 30 days, or even at least about 60 days or longer.
- compositions comprising bovine somatotropin associated with zinc have been found to provide, for at least about 7 days in the serum of a lactating cow injected with a 2.5 milliliter dose thereof, an average bovine somatotropin concentration of at least about 12 ng/ml, which is highly advantageous for purposes of enhancing milk production and/or feed-to-milk conversion efficiency in cattle.
- a composition containing at least about 300 mg of a zinc-associated somatotropin is desirable to provide such an increased serum level of active bovine somatotropin for at least about 15 days.
- the zinc-associated somatotropin is advantageously present in a high enough concentration (e.g. at least about 15%) to permit the use of a conveniently small volume of the composition (e.g. about 10 ml or less, say between about 1 and about 3 ml) for ease of administration.
- compositions of this invention can include steroid and/or non-steroid anti-inflammatory agents which preferably are in the composition at a level low enough to avoid any systemic effect but sufficient to be effective in reducing local inflammation.
- Somatotropins associated with polyvalent metal can be prepared by reacting the dissolved somatotropin with non-toxic metal (e.g. zinc) ions.
- metal-associated somatotropin is prepared by adding the metal, optionally in the form of a low water-solubility salt thereof, but generally preferably as a water-soluble salt thereof (e.g. zinc chloride) to a buffered solution of the somatotropin to precipitate the somatotropin associated with the metal.
- organic solubilizing compounds e.g. urea or guanidine
- solubilizing compounds e.g. urea or guanidine
- concentration of the solubilizing compound and/or pH of the solution may be critical in maintaining a bioactive conformation of the somatotropin.
- the pH of the solution is generally critical to recovery of the resulting metal-associated somatotropin generally as a precipitate.
- Temperatures are preferably kept low, e.g. generally no higher than about room temperature, to avoid denaturing.
- depyrogenation and/or sterilization may be desirable.
- Pyrogens e.g. endotoxins
- ion-exchange resin Most pyrogens will bond to positively charged sites, e.g. on a cation exchange resin. Some pyrogens may bind to negatively charged sites. Accordingly, a mixed bed of ion-exchange resin beads is useful in ensuring sufficient removal of pyrogens.
- the somatotropin solution can be sterilized to remove non-sterile foreign bodies such as bacteria or loose contaminates from earlier processing by filtration through a fine filter, e.g. 0.2 micrometre mesh.
- the depyrogenated, sterilized somatotropin solution is then contacted with a non-toxic metal solution to precipitate the metal-associated somatotropin usually desirably forming a suspension.
- the rate of metal addition affects particle size of the resulting metal-associated somatotropin .
- Metal addition can be controlled by adjusting metal concentration in the solution added, volumetric flow rate and/or dispersion rate.
- the suspension of metal-associated somatotropin can be diluted to reduce the tendency to increase particle size, e.g. by agglomeration.
- the metal-associated somatotropin then be recovered by multiple centrifuging and washing to remove excess metal and anions, followed by lyophilization.
- Somatotropins associated with a monovalent metal can be prepared by lyophilization of a solution of the somatotropin and the metal ion.
- a somatotropin e.g. bovine
- a somatotropin can be dissolved in a variety of buffered solutions.
- it is dissolved in an aqueous urea solution buffered with tris(hydroxymethyl) amino methane (TRIS) or other suitable buffering agent.
- TIS tris(hydroxymethyl) amino methane
- a desirable upper limit of urea concentration is usually about 6M; in some cases a urea concentration of about 4.5M is preferred.
- Lower urea concentrations, say 3M or as low as 2M or even 1M, can be used but with lower solubility of the somatotropin.
- the pH of the buffered urea solution is preferably between about 7 and about 10.5. Between these pH limits the recovery of somatotropin precipitated from solution is typically at least about 60%. Generally, higher recovery (e.g. at least 90%) can be achieved with a pH between about 9 and about 9.5.
- the temperature of the solution throughout the precipitation should be sufficiently low to prevent oligomerization of the somatotropin. Generally such temperatures are desirably lower than about 10° and more preferably lower than about 5°.
- the solution (depyrogenated and sterilized as aforesaid) is treated by diafiltration (or dialysis) to exchange the urea with a solution of the metal bicarbonate (e.g. a 25 mM NaHCO 3 solution, pH 9.5) or other suitable salt. Multiple exchanges with the bicarbonate solution are preferably conducted to ensure complete exchange of urea.
- the solution is then treated by further diafiltration with water to remove excess NaHCO 3 which is indicated by the start of precipitation of MBS. Recovery of sodium-somatotropin by lyophilization produces a powder of the sodium salt of the somatotropin.
- the solution depyrogenated and sterilized as aforesaid
- a polyvalent (e.g. zinc) salt e.g. zinc
- Use of a 1M solution of zinc chloride has been found to produce acceptable precipitated zinc-somatotropin from 4.5M urea solution of the somatotropin, although higher or lower concentrations of the chloride can be utilized.
- the ZnCl 2 solution is preferably added slowly, e.g. as by titration, while stirring the somatotropin solution.
- the somatotropin solution reaches first an off-white, then pearly-white color as the stoichiometric amount of ZnCl 2 is added.
- the somatotropin solution reaches first an off-white, then pearly-white color as the stoichiometric amount of ZnCl 2 is added.
- additional ZnCl 2 e.g. up to about 10 ml of 1M ZnCl 2 solution
- the suspension is then often desirably diluted to reduce the tendency to increase particle size of the precipitate. Dilution with up to about 3.5 volumes of water to about 1M urea has been found satisfactory to keep the zinc-somatotropin particles from agglomerating. Recovery by diafiltration (or multiple centrifuging and washing) to remove urea, TRIS and zinc and chlorine ions, followed by lyophilization, produces a powder having particle sizes generally less than between 10 and 20 micrometres.
- the particles When the somatotropin is bovine, the particles typically contain between about 0.3 and about 1% zinc (between about 1 and 4 molecules of zinc per molecule of somatotropin). If zinc addition rate is increased, higher amounts are found in the precipitate, e.g. up to 4-5%. Such higher amounts may be due to additional binding of zinc to active acid sites on the somatotropin, e.g. at additional aspartic and/or glutamic acid residues or possibly at histidine residues, or at the carboxy terminus of the somatotropin It is not intended that this theory of zinc binding be considered limiting to the scope of this invention. In general, precipitation using an essentially minimum amount of zinc is considered preferable.
- This example illustrates the preparation of a zinc-associated bovine somatotropin of this invention.
- MFS Methionine N-terminated bovine somatotropin
- the bacteria were killed by treatment with 50% sulfuric acid sufficient to lower pH of the fermentation broth to 1.7.
- the broth was neutralized with NaOH and centrifuged, leaving a cell paste which was suspended in urea, homogenized, cooled to about 4° (that temperature was maintained until the MBS lyophilization referred to below), centrifuged and washed three times, dissolved in guanidine hydrochloride (7M), centifuged to remove insolubles, filtered, passed through a G25 Sephadex column in which the guanidine was exchanged for urea, filtered and then passed through a DE52 ion exchange column.
- the volume of the effluent was reduced about 30X by hollow fiber ultrafiltration.
- the concentrated solution was passed through a G75 Sephadex chromatography column, another hollow fiber volume reduction step and then dialyzed to exchange the urea first for NaHCO 3 solution and then distilled water to precipitate the MBS.
- the precipitate was lyophilized, leaving a white solid (slightly soluble in water) containing a polypeptide (MBS) having the NH 2 -met-phe(1)-pro(2)... leu(126)... phe(190)-COOH amino acid sequence expressed in the aforementioned publication by Seeburg et al.
- Such MBS was dissolved in a 4.5M urea, 0.09M TRIS solution at 21.5 mg MBS per ml, 4° and pH 9.5.
- the MBS solution was depyrogenated by mixing with 0.2 grams of mixed anionic/cationic ion exchange resin beads (Biorad AG-501X8) for each ml of sterile MBS solution. The mixture was stirred for about 10 minutes at 4° and then filtered with a 1 micrometre nylon filter to remove the beads containing adsorbed pyrogens.
- the depyrogenated MBS was sterilized by passing the solution through a radiation sterilized, pleated capsule filter having 0.2 micrometres mesh to remove non-sterile foreign bodies such as bacteria or loose contaminates from earlier processing.
- the MBS was converted to a zinc salt (ZnMBS) by adding 1M ZnCl 2 while stirring the depyrogenated MBS solution.
- ZnMBS zinc salt
- the precipitated ZnMBS contained approximately 1% zinc.
- the solution containing ZnMBS solids was then diluted with sterile depyrogenated water to an urea concentration of 1M.
- ZnMBS was recovered by centrifuging at 10,000 x g for 30 min. while maintaining the solution at 4° .
- the ZnMBS was suspended in sterile depyrogenated water at 50mg ZnMBS/ml using high shear mixing.
- ZnMBS was again recovered by centrifuging at 10,000 x g for 30 min, resuspended in sterile depyrogenated water at 50mg ZnMBS/ml using high shear mixing, and then lyophilized to produce a white fluffy powder of sterile ZnMBS.
- This example illustrates an alternative preparation of ZnMBS.
- a depyrogenated and sterilized solution of 21 mg of MBS per ml in 4.5 M urea, 0.05M TRIS, 10° and pH 8.8 was recirculated through a hold tank by a positive displacement pump. 1M ZnCl 2 was added at the pump suction until the concentration of the solution was 0.01 M ZnCl 2 resulting in precipitation of ZnMBS. Dilution water was added to provide a concentration of 10mg MBS per ml resulting in further precipitation of ZnMBS.
- the resulting suspension of ZnMBS was then circulated at 25° through a diafiltration hollow fiber membrane, having pores which would pass molecules of up to 100,000 MW, until the concentration reached 40 mg MBS per ml; then water was added to match the membrane filtrate rate until essentially all of the Zn, urea and TRIS was removed from the suspension. Water addition was stopped to allow concentration to about 80 mg MBS per ml.
- the concentrated suspension was then lyophilized to provide a dry, white powder of ZnMBS having particle sizes in the range of 0.5 to 11 micrometres.
- This example illustrates the preparation of a sodium-associated bovine somatotropin.
- a depyrogenated and sterilized solution of 21.5 mg per ml in 4.5 M urea, 0.05M TRIS, 4° and pH 9.5 was dialyzed to exchange urea first for NaHCO 3 solution and then distilled water. The water exchange was stopped when the MBS begins to precipitate. The solution was then filtered with a 0.2 micrometres filter to remove precipitated MBS and lyophilized to provide a sodium salt (NaMBS) which can be used in compositions of this invention.
- NaMBS sodium salt
- This example illustrates the preparation of a composition of this invention containing a zinc-associated somatotropin.
- a volume of sesame oil (Fisher NF Grade) was added to a three-necked round bottom flask.
- An antihydration agent (AlMS) at 5% of total AlMS and sesame oil was added.
- the flask was placed in an oil bath at 155° and stirred to disperse the AlMS as rapidly as possible. Stirring continued for 20 minutes, during which the AlMS dissolved completely in the oil.
- the flask was removed from the bath, kept under vacuum and allowed to cool to 25°. On cooling, the solution converted to a thick gel.
- the cooled gel was fed into a ball mill having a high-shear agitator in-a bed of stainless steel balls having 1/8, 3/16 and 1/4 inch (0.32, 0.48 and 0.64 cm) diameters.
- This example illustrates an efficacious use of a composition of this invention in prolonged release of a bovine somatotropin, to enhance milk production in lactating dairy cattle.
- a substantially non-aqueous composition was prepared essentially as in Example 2 by dissolving 5% AlMS in sesame oil heated to 155°. The oil was cooled to form a gelled oil. ZnMBS was dispersed and milled in the oil until the composition contained 32% ZnMBS in a continuous phase of the oil (9.4 wt. ratio of ZnMBS to AlMS). Syringes equipped with 18 gauge, 1.5 inch (3.8 cm) long needles were loaded with 2.54 grams (2.5 ml) of composition to provide a dose containing 805 mg ZnMBS. The composition had a syringeability of 0.36 ml/sec. Blank compositions of 5% AlMS in sesame oil without the polypeptide were also prepared and loaded at 2.4 grams into identical syringes.
- compositions were injected into 23 Holstein dairy cattle in the second or third trimester of their second (or subsequent) lactation.
- the cattle were randomly organized into 4 groups of 5 or 6.
- Two groups were injected intramuscularly (IM) in the gluteal region, one with the ZnMBS-containing composition and the other (a control group) with the blank composition.
- two other groups were injected subcutaneously (SQ) in the suprascapular region with the ZnMBS-containing or blank composition.
- Cumulative least-square means for average milk production (covariantly adjusted for differences in pretreatment milk yields) are shown in Table 1, where milk production is expressed in kilograms of milk per day.
- Table 1 Cumulative least-square means for average milk production (covariantly adjusted for differences in pretreatment milk yields) are shown in Table 1, where milk production is expressed in kilograms of milk per day.
- Table 1 a single IM or SQ injection of a conveniently-administered composition of this invention provides a rapid and prolonged improvement in milk production at very high levels of statistical significance.
- RIA radioimmunoassay
- compositions of this invention for prolonged release of a somatotropin (MBS) in animals using a variety of materials in such compositions.
- MFS somatotropin
- ZnMBS compositions were formulated essentially as disclosed in Example 3 using combinations of the following constituents:
- compositions listed in Table 3 were administered to 16 groups of 8 immunosuppressed female Sprague-Dawley (IFS-D) rats. TABLE 3 Group Dose Volume, Microliters Injected Compositions Oil AlMS,% (a) ZnMBS, % Wt.
- Such plasma levels are shown in Table 4 for blood samples taken prior to injection on day 0 (the injection day).
- Some baseline measurements for rats in Examples 4-7 are higher than some baseline and released polypeptide measurements for cows in Example 3. This is partly because of interspecies differences in normal somatotropin levels and partly because the RIA in Example 3 was more precise).
- compositions of this invention for prolonged release of MBS utilizing other fatty acid salts of aluminum as antihydration agents.
- AlML aluminum monolaurate
- AlMP aluminum monopalmitate
- gelled oils containing 3% of AlML or AlMP were prepared essentially as in Example 4.
- ZnMBS was suspended In the gelled oils at a concentration of 30% of the total composition (14.3 wt. ratio of ZnMBS to AlML or AlMP).
- Each composition was injected into a group of 8 IFS-D rats at the dosages indicated in Table 5.
- compositions of this invention for prolonged release of MBS utilizing olive oil or corn oil.
- gelled oils were prepared essentially as in Example 4 utilizing 3% AlMS based on AlMS plus the oil.
- the suspensions of 30% or 40% ZnMBS were injected into two groups of 8 IFS-D rats at the dosages indicated in Table 7.
- compositions of this invention comprising about 10% of the somatotropins MBS and ZnMBS, in peanut oil.
- This example further illustrates that prolonged effect of the somatotropin can be enhanced by using the somatotropin associated with a metal and by use of an antihydration agent.
- Compositions as indicated in Table 9 for injection were prepared essentially as in Example 4. TABLE 9 Injected Compositions Group Somatotropin Somatotropin Loading, % Oil AlMS,% (a) 30 MBS 10 peanut - 31 ZnMBS 10 peanut - 32 MBS 10 peanut 1 33 ZnMBS 10 peanut 1 (a) Based on weight of oil plus AlMS.
- Each composition was injected subcutaneously into a group of 8 IFS-D rats at a dosage of 300 microliters. Analysis of blood samples taken from the rats on the indicated days after injection indicated plasma concentrations as shown in Table 10, where the readings on day 0 are baseline for the analyses. Table 10 Average Bovine Somatotropin Concentrations in Plasma, ng/ml Group Days After Injection 0 1 3 5 7 11 14 30 14 1350 375 145 75 50 20 31 15 1800 310 240 200 40 20 32 12 1200 250 123 64 35 21 33 18 620 350 330 280 175 125 Comparison of the results for Groups 30 and 31 illustrates enhancement of prolonged release of MBS for at least 7 days by use of an associated polyvalent metal. Comparison of the results for Groups 32 and 33 illustrates enhancement of prolonged release of MBS by use of an antihydration agent when the MBS is associated with such a polyvalent metal.
- compositions of this invention containing 10% bovine somatotropin without the presence of an antihydration agent in each of the following oils: sesame, peanut, corn, olive, safflower, cotton seed, palm, rapeseed and soybean. Separate volumes of each oil are maintained at each of the following temperatures: 4°, 25°, 50°, 75°, 100° and 125°.
- ZnMBS is dispersed and milled in each oil as in Example 2 until its concentration reaches 10%. Milling is continued until the somatotropin has a median particle diameter no greater than 15 micrometres.
- Each composition has a syringeability greater than 0.1 ml/sec.
- compositions of this invention prepared as in Example 8 except that prior to adding the somatotropin.
- AlMS is dispersed in each oil in a concentration of 5% based on the oil plus AlMS.
- These compositions have a syringeability greater than 0.1 ml/sec.
- compositions of this invention prepared as in Example 8 except that addition of the somatotropin is continued until the compositions contain 40% bovine somatotropin. Dispersion and milling are continued until the somatotropin has a median particle diameter no greater than 15 micrometres. These compositions have a syringeability greater than 0.03 ml/sec.
- compositions of this invention prepared as in Example 10 except that prior to adding the somatotropin, AlMS is dispersed in each oil in a concentration of 5% based on the oil plus AlMS. These compositions have a syringeability greater than 0.03 ml/sec.
- compositions of this invention containing 10% of a bovine somatotropin in each of the following oils: sesame, corn, olive, safflower, cotton seed, palm, rapeseed and soybean. Each oil is heated to 160° and stirred to facilitate dissolving AlMS. When 1% AlMS is dissolved, each oil is cooled to 25° . ZnMBS is dispersed and milled in the cooled oil as in Example 2 until its concentrationreaches 10% and its median particle diameter is reduced to not greater than 15 micrometres. Each composition has a syringeability greater than 0.1 ml/sec.
- compositions of this invention prepared as in Example 12 except that addition of the somatotropin is continued until each composition contains 40% somatotropin.
- the compositions are milled as an Example 2 until the somatotropin has a median particle diameter no greater than 15 micrometres .
- Each composition has a syringeability greater than 0.03 ml/sec.
- compositions of this invention containing 10% of a bovine somatotropin in the following oils having AlMS dissolved therein in a concentration of 5% based on the oil plus AlMS: sesame, peanut, corn, safflower, cotton seed, palm, rapeseed and soybean. Each oil is heated to 160° and stirred to facilitate dissolving the AlMS. When the AlMS is dissolved, each oil is cooled to 25°. ZnMBS is then dispersed and milled in the cooled oil as in Example 2 until its concentration therein is 10%. The dispersion is further milled until the somatotropin has a median particle diameter not greater than 15 micrometres. Each composition has a syringeability greater than 0.1 ml/sec.
- compositions of this invention containing 42% of a bovine somatotropin are prepared by continuing addition of the somatotropin to compositions of Example 14 until each composition contains 42% somatotropin. While still maintaining the oil as a continuous phase the somatotropin is dispersed and milled as in Example 2 until it has a median particle diameter not greater than 15 micrometres. Each composition has a syringeability greater than 0.03 ml/sec.
- compositions of this invention containing 20% of a bovine somatotropin in oils similar to those used in Example 9 but in which one of the following antihydration agents is substituted for the AlMS: aluminum distearate or tristearate; aluminum mono-, di- or tripalmitate or -laurate; magnesium mono- or distearate, -laurate or -palmitate; and calcium mono- or distearate, -laurate or -palmitate.
- the antihydration agent is added to the oil prior to addition of the somatotropin.
- ZnMBS is added as in Example 2 until its concentration is 20%. Dispersion and milling are continued until the somatotropin has a median particle diameter no greater than 15 micrometres.
- Each composition has a syringeability greater than 0.03 ml/sec.
- composition of this invention containing other concentrations of a bovine somatotropin in oils similar to Example 20 where the oils of the kind used in Example 16 except that the addition of the somatotropin is continued until its concentration is 25%, 30% or 35%. Dispersion and milling are continued until the somatotropin has a median particle diameter no greater than 15 micrometres. Each composition has a syringeability greater than 0.03 ml/sec.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Feed For Specific Animals (AREA)
- Fodder In General (AREA)
- Fats And Perfumes (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Paper (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
- Holo Graphy (AREA)
Claims (37)
- Composition pratiquement non aqueuse, comprenant une somatotrophine biologiquement active et, comme phase continue de cette composition, une huile biocompatible, caractérisée en ce que la composition est destinée à l'administration parentérale et en ce que la quantité de somatotrophine est d'au moins 10 % en poids de la composition.
- Composition selon la revendication 1, dans laquelle la somatotrophine est une somatotrophine de bovin.
- Composition selon la revendication 1, dans laquelle la somatotrophine est une somatotrophine de porcin.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition comprend au moins 15 % de somatotrophine.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition comprend de 15 % à 42 % de somatotrophine.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition comprend au moins 20 % de somatotrophine.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle la composition comprend en outre au moins 1 % en poids d'un agent anti-hydratation.
- Composition selon la revendication 7, dans laquelle l'agent anti-hydratation est un sel d'aluminium, de calcium ou de magnésium d'un acide gras en C8 à C22.
- Composition selon la revendication 8, dans laquelle l'acide gras est choisi parmi l'acide stéarique, l'acide palmitique, l'acide laurique et des mélanges de ceux-ci.
- Composition selon la revendication 7, 8 ou 9, dans laquelle le rapport pondéral de la somatotrophine à l'agent anti-hydratation est au moins égal à 1.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle la somatotrophine est associée à un ion métallique non toxique.
- Composition selon la revendication 11, dans laquelle le métal est choisi parmi le zinc, le sodium, le potassium, le fer, le calcium, le bismuth, le baryum, le magnésium, le manganèse, l'aluminium, le cuivre, le cobalt, le nickel et le cadmium.
- Composition selon la revendication 12, dans laquelle le métal est le zinc.
- Composition selon la revendication 12, dans laquelle le métal est le sodium ou le potassium.
- Composition selon l'une quelconque des revendications précédentes, ayant une aptitude à l'administration par seringue d'au moins 0,03 millilitre par seconde, l'aptitude à l'administration par seringue étant le volume de la composition, en millilitres, qui traverse une aiguille hypodermique ayant un diamètre interne de 0,838 mm et une longueur de 4 cm en une seconde lorsqu'on exerce sur la composition une pression de 1193 kPa dans une seringue munie de l'aiguille.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle les particules de somatotrophine ont un diamètre volumique médian non supérieur à 15 micromètres.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle les particules de somatotrophine ont un diamètre volumique médian non supérieur à 10 micromètres.
- Composition selon l'une quelconque des revendications précédentes, dans laquelle l'huile est choisie parmi l'huile de maïs, l'huile d'arachide, l'huile de sésame, l'huile d'olive, l'huile de palme, l'huile de carthame, l'huile de soja, l'huile de coton, l'huile de colza et des mélanges de celles-ci.
- Composition pratiquement non aqueuse pour l'administration parentérale, comprenant entre 15 et 42 % en poids d'une somatotrophine de bovin, entre 2 % et 5 % en poids d'un mono- ou distéarate d'aluminium, et comme phase continue de la composition, une huile végétale biocompatible, les particules de cette somatotrophine ayant un diamètre volumique médian non supérieur à 10 micromètres et le rapport pondéral de cette somatotrophine à ce stéarate valant au moins 3.
- Composition selon la revendication 19, dans laquelle la somatotrophine est chimiquement associée à du zinc.
- Composition selon la revendication 19 ou 20, dans laquelle le diamètre volumique médian des particules n'est pas supérieur à 5 micromètres.
- Composition selon l'une quelconque des revendications précédentes, destinée à être utilisée dans un procédé permettant de réaliser une libération prolongée d'une somatotrophine biologiquement active dans le système circulatoire d'un animal auquel la composition a été administrée par voie parentérale.
- Composition selon l'une quelconque des revendications précédentes, destinée à être utilisée dans un procédé permettant d'améliorer la proportion viande/graisse, l'efficience de l'alimentation ou la production laitière d'un animal auquel la composition a été administrée par voie parentérale.
- Composition selon la revendication 22 ou 23, dans laquelle l'animal est choisi parmi les bovins, les moutons, les chèvres et les porcs.
- Traitement non-thérapeutique et non-diagnostique d'un animal, qui comprend l'administration parentérale à cet animal d'une composition selon l'une quelconque des revendications 1 à 21, pour réaliser une libération prolongée d'une somatotrophine biologiquement active dans le système circulatoire de cet animal.
- Procédé pour améliorer la proportion viande/graisse, l'efficience de l'alimentation ou la production laitière d'un animal, qui comprend l'administration parentérale à cet animal d'une composition selon l'une quelconque des revendications 1 à 21.
- Procédé permettant de maintenir, chez une vache allaitante, une concentration plasmatique moyenne de somatotrophine d'au moins 12 nanogrammes par millilitre pendant au moins 7 jours, qui comprend l'administration parentérale d'une composition selon l'une quelconque des revendications 1, 2, et 4 à 21, qui contient une somatotrophine de bovin.
- Procédé selon la revendication 25 ou 26, dans lequel l'animal est choisi parmi les bovins, les moutons, les chèvres et les porcs.
- Procédé de préparation d'une composition de somatotrophine non aqueuse, comprenant le fait de disperser, en particules distinctes finement divisées, de la somatotrophine dans une huile biocompatible, dans des proportions telles que l'huile forme la phase continue de la dispersion obtenue et que cette dispersion contienne au moins 10 % en poids de cette somatotrophine, et dans des conditions telles que la dispersion obtenue soit pratiquement non aqueuse et que les particules de somatotrophine présentes dans la dispersion obtenue ait un diamètre volumique médian non supérieur à 15 micromètres, cette dispersion étant effectuée à des températures compatibles avec l'activité biologique de la somatotrophine.
- Procédé selon la revendication 29, dans lequel un agent anti-hydratation est présent dans l'huile, à raison de 1 % à 5 % du poids de l'huile et de l'agent anti-hydratation, cet agent anti-hydratation comprenant un sel métallique d'un acide gras en C8 à C22, le métal étant choisi parmi l'aluminium, le calcium et le magnésium.
- Procédé selon la revendication 29 ou 30, dans lequel l'huile est choisie parmi l'huile de maïs, l'huile d'arachide, l'huile de sésame, l'huile d'olive, l'huile de palme, l'huile de carthame, l'huile de soja, l'huile de coton, l'huile de colza et des mélanges de celles-ci.
- Procédé selon la revendication 30, dans lequel l'acide gras est choisi parmi l'acide stéarique, l'acide palmitique, l'acide laurique et des mélanges de ceux-ci.
- Procédé selon l'une quelconque des revendications 29 à 32, dans lequel la dispersion est effectuée entre 4°C et 125°C.
- Procédé selon l'une quelconque des revendications 29 à 33, dans lequel la somatotrophine est une somatotrophine de bovin ou de porcin.
- Utilisation d'une somatotrophine animale dans la fabrication d'une composition pour améliorer la proportion viande/graisse, l'efficience de l'alimentation ou la production laitière d'un animal, cette composition comprenant, comme phase continue, une huile biocompatible, et comme phase discontinue, la somatotrophine animale en une proportion non inférieure à 10 % en poids de la composition.
- Utilisation d'un somatotrophine animale selon la revendication 35, dans laquelle la composition présente les caractéristiques indiquées dans l'une quelconque des revendications 1 à 3 et 4 à 21.
- Utilisation d'une somatotrophine animale selon la revendication 35 ou 36, dans laquelle l'animal est choisi parmi les bovins, les moutons, les chèvres et les porcs.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP89113657A EP0343696B1 (fr) | 1984-10-04 | 1985-10-03 | Zinc-somatotropines |
AT85870135T ATE62598T1 (de) | 1984-10-04 | 1985-10-03 | Verzoegerte freisetzung biologisch aktiver somatotropine. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US65771384A | 1984-10-04 | 1984-10-04 | |
US657713 | 1996-05-30 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89113657A Division EP0343696B1 (fr) | 1984-10-04 | 1985-10-03 | Zinc-somatotropines |
EP89113657.4 Division-Into | 1985-10-03 |
Publications (4)
Publication Number | Publication Date |
---|---|
EP0177478A2 EP0177478A2 (fr) | 1986-04-09 |
EP0177478A3 EP0177478A3 (en) | 1987-04-01 |
EP0177478B1 EP0177478B1 (fr) | 1991-04-17 |
EP0177478B2 true EP0177478B2 (fr) | 1997-03-05 |
Family
ID=24638364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP85870135A Expired - Lifetime EP0177478B2 (fr) | 1984-10-04 | 1985-10-03 | Libération prolongée de somatotropines biologiquement actifs |
Country Status (28)
Country | Link |
---|---|
US (2) | US5013713A (fr) |
EP (1) | EP0177478B2 (fr) |
JP (1) | JPH0745409B2 (fr) |
KR (1) | KR890002631B1 (fr) |
CN (2) | CN1007124B (fr) |
AT (1) | ATE132372T1 (fr) |
AU (1) | AU573904B2 (fr) |
BG (1) | BG47039A3 (fr) |
CA (1) | CA1309018C (fr) |
CS (1) | CS274717B2 (fr) |
CZ (1) | CZ284472B6 (fr) |
DD (1) | DD244914A5 (fr) |
DE (2) | DE3582548D1 (fr) |
DK (1) | DK449585A (fr) |
ES (1) | ES8702440A1 (fr) |
GE (1) | GEP19960332B (fr) |
GR (1) | GR852398B (fr) |
HU (1) | HU196714B (fr) |
IE (1) | IE65392B1 (fr) |
IL (1) | IL76554A (fr) |
NO (1) | NO173975C (fr) |
NZ (1) | NZ213701A (fr) |
PL (2) | PL261273A1 (fr) |
PT (2) | PT81248B (fr) |
SU (1) | SU1595330A3 (fr) |
UA (1) | UA8352A1 (fr) |
YU (1) | YU45281B (fr) |
ZA (1) | ZA857642B (fr) |
Families Citing this family (299)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5086041A (en) * | 1984-10-04 | 1992-02-04 | Monsanto Company | Methods of using prolonged release somatotropin compositions |
US5411951A (en) * | 1984-10-04 | 1995-05-02 | Monsanto Company | Prolonged release of biologically active somatotropin |
KR890002631B1 (ko) * | 1984-10-04 | 1989-07-21 | 몬산토 캄파니 | 생물학적으로 활성인 소마토트로핀을 지속적으로 유리하는 조성물 |
US5474980A (en) * | 1984-10-04 | 1995-12-12 | Monsanto Company | Prolonged release of biologically active somatotropins |
US5037806A (en) * | 1985-02-22 | 1991-08-06 | Monsanto Company | Biologically active method using somatotropins |
US4775659A (en) * | 1985-08-19 | 1988-10-04 | Eli Lilly And Company | Injectable semi-solid formulations |
IL79765A (en) * | 1985-08-23 | 1992-02-16 | Lilly Co Eli | Injectable sustained release formulations of bovine somatotropin |
US4977140A (en) * | 1985-08-23 | 1990-12-11 | Eli Lilly And Company | Injectable sustained release formulation |
US4857506A (en) * | 1987-01-12 | 1989-08-15 | American Cyanamid Company | Sustained release growth hormone compositions for parenteral administration and their use |
EP0279616A3 (fr) * | 1987-02-17 | 1990-03-07 | International Minerals And Chemical Corporation | Augmentation de la croissance du porc |
US4863736A (en) | 1987-03-16 | 1989-09-05 | Monsanto Company | Somatotropin prolonged release |
GB8725427D0 (en) * | 1987-10-30 | 1987-12-02 | Lilly Industries Ltd | Somatotropin formulations |
US5021554A (en) * | 1989-02-24 | 1991-06-04 | Eli Lilly And Company | Process for protein particle size reduction using a fluid-energy mill |
US5780599A (en) * | 1990-07-13 | 1998-07-14 | Novo Nordisk A/S | Growth hormone crystals and a process for production of growth hormone crystals |
DK168790D0 (fr) * | 1990-07-13 | 1990-07-13 | Novo Nordisk As | |
US6894023B1 (en) | 1990-07-13 | 2005-05-17 | Novo Nordisk A/S | Growth hormone crystals and a process for production of these GH-crystals |
YU87892A (sh) * | 1991-10-01 | 1995-12-04 | Eli Lilly And Company Lilly Corporate Center | Injektibilne formulacije produženog otpuštanja i postupci za njihovo dobijanje i primenu |
US6063910A (en) * | 1991-11-14 | 2000-05-16 | The Trustees Of Princeton University | Preparation of protein microparticles by supercritical fluid precipitation |
DK0661989T3 (da) * | 1992-09-21 | 1998-03-02 | Upjohn Co | Proteinsammensætninger med vedvarende frigivelse |
AU694419B2 (en) * | 1993-03-12 | 1998-07-23 | Zoetis P&U Llc | Crystalline ceftiofur free acid |
US6284727B1 (en) | 1993-04-07 | 2001-09-04 | Scios, Inc. | Prolonged delivery of peptides |
US6087324A (en) | 1993-06-24 | 2000-07-11 | Takeda Chemical Industries, Ltd. | Sustained-release preparation |
ZA949350B (en) | 1994-01-25 | 1996-05-24 | Upjohn Co | Aqueous prolonged release formulation |
ES2151079T3 (es) * | 1994-09-09 | 2000-12-16 | Takeda Chemical Industries Ltd | Preparacion de liberacion sostenida que contiene una sal metalica de un peptido. |
CA2240685A1 (fr) | 1996-01-11 | 1997-07-17 | Pharmacia & Upjohn Company | Formulation aqueuse a liberation prolongee |
US5767080A (en) * | 1996-05-01 | 1998-06-16 | Cargill, Incorporated | Enhanced milk production in dairy cattle |
KR20080011353A (ko) | 2000-02-24 | 2008-02-01 | 몬산토 테크놀로지 엘엘씨 | 소마토트로핀의 지속적인 방출을 위한 비수성 주사제제들 |
MXPA03000073A (es) * | 2000-06-26 | 2003-09-25 | Monsanto Technology Llc | Formulaciones que contienen agente tensioactivo no acuoso para la liberacion prolongada de somatrotopina. |
US6664234B1 (en) * | 2000-06-30 | 2003-12-16 | Monsanto Technology Llc | Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin |
JP2004515467A (ja) | 2000-08-07 | 2004-05-27 | ネクター セラピューティックス | 吸入可能な、噴霧乾燥した、最少の凝集物を有する4−ヘリックスバンドルタンパク質粉末 |
US7829100B2 (en) * | 2000-09-12 | 2010-11-09 | Teagarden Dirk L | Pharmaceutical composition having modified carrier |
DE10161078A1 (de) * | 2001-12-12 | 2003-08-28 | Achim Goepferich | Matrizes zur Stabilisierung und kontrollierten Freisetzung von Problemarzneistoffen |
US7659061B2 (en) * | 2002-11-19 | 2010-02-09 | Pharmacia & Upjohn Company | Pharmaceutical compositions having a modified vehicle |
JP2006199589A (ja) * | 2003-09-03 | 2006-08-03 | Ltt Bio-Pharma Co Ltd | 生理活性タンパク質またはペプチドを含有するナノ粒子およびその製造方法、ならびに当該ナノ粒子からなる外用剤 |
EP1866319B1 (fr) | 2005-04-01 | 2011-11-23 | The Regents of The University of California | Nucleosides phosphono-pent-2-en-1-yle et analogues |
US20090156545A1 (en) * | 2005-04-01 | 2009-06-18 | Hostetler Karl Y | Substituted Phosphate Esters of Nucleoside Phosphonates |
GB0511269D0 (en) | 2005-06-02 | 2005-07-13 | Creative Peptides Sweden Ab | Sustained release preparation of pro-insulin C-peptide |
RU2457854C2 (ru) | 2005-12-30 | 2012-08-10 | Цзэньсунь (Шанхай) Сайенс Энд Текнолоджи Лимитед | Длительное высвобождение нейрегулина для улучшения сердечной функции |
WO2007106494A2 (fr) * | 2006-03-13 | 2007-09-20 | Encysive Pharmaceuticals, Inc. | Procedes et compositions pour le traitement d'une insuffisance cardiaque diastolique |
CA2644784A1 (fr) * | 2006-03-13 | 2007-09-20 | Jinling Chen | Formulations de sitaxsentan sodium |
CN101443314B (zh) * | 2006-03-13 | 2014-04-09 | 杏林制药株式会社 | 作为gsk-3抑制剂的氨基喹诺酮类 |
US20080026061A1 (en) * | 2006-06-22 | 2008-01-31 | Reichwein John F | Crystalline N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4.5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide |
PT2066662E (pt) | 2006-09-21 | 2013-02-13 | Kyorin Seiyaku Kk | Inibidores de serina-hidrolase |
EP2081893B1 (fr) | 2006-10-19 | 2011-03-23 | Auspex Pharmaceuticals, Inc. | Indoles substitués |
WO2008057604A2 (fr) * | 2006-11-08 | 2008-05-15 | The Regents Of The University Of California | Agents thérapeutiques contenant de petites molécules, synthèses d'analogues et de dérivés et leurs procédés d'utilisation |
PL2144604T3 (pl) * | 2007-02-28 | 2012-02-29 | Conatus Pharmaceuticals Inc | Sposoby leczenia przewlekłego zapalenia wątroby typu C z zastosowaniem RO 113-0830 |
WO2008106167A1 (fr) * | 2007-02-28 | 2008-09-04 | Conatus Pharmaceuticals, Inc. | Polythérapie incluant des inhibiteurs de métalloprotéinases matricielles et des inhibiteurs de caspases pour le traitement de maladies hépatiques |
DK2125698T3 (en) | 2007-03-15 | 2016-11-07 | Auspex Pharmaceuticals Inc | Deuterated d9-VENLAFAXINE |
US7892776B2 (en) | 2007-05-04 | 2011-02-22 | The Regents Of The University Of California | Screening assay to identify modulators of protein kinase A |
CN101801188A (zh) * | 2007-07-12 | 2010-08-11 | 特拉加拉医药品公司 | 治疗癌症、肿瘤和肿瘤相关性疾病的方法和组合物 |
CN101855228B (zh) * | 2007-09-11 | 2012-10-24 | 杏林制药株式会社 | 作为gsk-3抑制剂的氰基氨基喹诺酮和四唑并氨基喹诺酮 |
EP2203459B1 (fr) | 2007-09-12 | 2016-03-16 | Kyorin Pharmaceutical Co., Ltd. | Aminoquinolones spirocycliques utilisées en tant qu'inhibiteurs de gsk-3 |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CA2972138A1 (fr) | 2008-03-17 | 2009-09-24 | Ambit Biosciences Corporation | Composes modulateurs de raf kinase et methodes d'utilisation associees |
US20090298882A1 (en) * | 2008-05-13 | 2009-12-03 | Muller George W | Thioxoisoindoline compounds and compositions comprising and methods of using the same |
AU2009249600A1 (en) * | 2008-05-20 | 2009-11-26 | Cerenis Therapeutics Holding S.A. | Niacin and NSAID for combination therapy |
CA2729168A1 (fr) | 2008-07-02 | 2010-02-04 | Idenix Pharmaceuticals, Inc. | Composes et compositions pharmaceutiques pour le traitement d'infections virales |
EP2324034A4 (fr) * | 2008-08-22 | 2012-05-16 | Orchid Chemicals & Pharm Ltd | Sel de sodium cristallin de l'antibiotique céphalosporine |
WO2010076329A1 (fr) | 2008-12-31 | 2010-07-08 | Scynexis, Inc. | Dérivés de cyclosporine a |
WO2010088450A2 (fr) | 2009-01-30 | 2010-08-05 | Celladon Corporation | Procédés de traitement de maladies associées à la modulation de serca |
US8568793B2 (en) | 2009-02-11 | 2013-10-29 | Hope Medical Enterprises, Inc. | Sodium nitrite-containing pharmaceutical compositions |
KR20110124787A (ko) | 2009-02-27 | 2011-11-17 | 암비트 바이오사이언시즈 코포레이션 | Jak 키나아제 조절 퀴나졸린 유도체 및 이의 사용 방법 |
JP5690286B2 (ja) | 2009-03-04 | 2015-03-25 | イデニク プハルマセウティカルス,インコーポレイテッド | ホスホチオフェン及びホスホチアゾールhcvポリメラーゼ阻害剤 |
EP2406266B1 (fr) * | 2009-03-11 | 2013-12-25 | Kyorin Pharmaceutical Co., Ltd. | 7-cycloalkylaminoquinolones comme inhibiteurs de la gsk-3 |
JP2012520314A (ja) | 2009-03-11 | 2012-09-06 | アムビト ビオスシエンセス コルポラチオン | 癌治療のためのインダゾリルアミノピロロトリアジンとタキサンの併用 |
WO2010110686A1 (fr) | 2009-03-27 | 2010-09-30 | Pathway Therapeutics Limited | Pyrimidinyl et 1,3,5-triazinyl benzimidazoles et leur utilisation en thérapie anticancéreuse |
CN102448958B (zh) | 2009-03-27 | 2015-10-21 | 维特Dc公司 | 嘧啶基和1,3,5-三嗪基苯并咪唑磺酰胺和其在癌症治疗中的用途 |
EP2727908A3 (fr) | 2009-04-22 | 2014-08-20 | Axikin Pharmaceuticals, Inc. | Antagonistes CCR3 d'arylsulfonamide 2,5-disubstitué |
NZ620092A (en) | 2009-04-22 | 2015-07-31 | Axikin Pharmaceuticals Inc | Arylsulfonamide ccr3 agtagonists |
NZ620074A (en) | 2009-04-22 | 2015-09-25 | Axikin Pharmaceuticals Inc | 2,5-disubstituted arylsulfonamide ccr3 antagonists |
WO2011003870A2 (fr) | 2009-07-06 | 2011-01-13 | Creabilis S.A. | Corticostéroïdes mini-pegylés, compositions les comprenant et procédés pour les préparer et les utiliser |
CA2767008C (fr) | 2009-07-07 | 2018-01-30 | Pathway Therapeutics, Inc. | Pyrimidinyl et 1,3,5-triazinyl benzimidazoles et leur utilisation dans le traitement du cancer |
CA2767168C (fr) | 2009-07-08 | 2019-04-09 | Hope Medical Enterprises, Inc. D.B.A. Hope Pharmaceuticals | Compositions pharmaceutiques contenant du thiosulfate de sodium |
EP2467144A1 (fr) | 2009-07-24 | 2012-06-27 | ViroLogik GmbH | Association d'inhibiteurs du protéasome et de médicaments anti-hépatite dans le traitement de l'hépatite |
TW201117812A (en) | 2009-08-05 | 2011-06-01 | Idenix Pharmaceuticals Inc | Macrocyclic serine protease inhibitors |
CN102470127A (zh) | 2009-08-19 | 2012-05-23 | 埃姆比特生物科学公司 | 联芳基化合物和其使用方法 |
TW201120037A (en) * | 2009-10-26 | 2011-06-16 | Sunesis Pharmaceuticals Inc | Compounds and methods for treatment of cancer |
WO2011056764A1 (fr) | 2009-11-05 | 2011-05-12 | Ambit Biosciences Corp. | Imidazo[2,1-b][1,3]benzothiazoles enrichis en isotopes ou fluores |
WO2011064769A1 (fr) | 2009-11-24 | 2011-06-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Procédés et compositions pharmaceutiques pour le traitement des bouffées de chaleur |
US20110301235A1 (en) | 2009-12-02 | 2011-12-08 | Alquest Therapeutics, Inc. | Organoselenium compounds and uses thereof |
RU2554087C2 (ru) | 2009-12-18 | 2015-06-27 | Айденикс Фармасьютикалз, Инк. | 5,5-конденсированные ариленовые или гетероариленовые ингибиторы вируса гепатита с |
CN104017063A (zh) | 2009-12-21 | 2014-09-03 | Ambrx公司 | 经过修饰的猪促生长素多肽和其用途 |
NZ600361A (en) | 2009-12-21 | 2014-06-27 | Ambrx Inc | Modified bovine somatotropin polypeptides and their uses |
US8710092B2 (en) * | 2009-12-23 | 2014-04-29 | Map Pharmaceuticals, Inc. | Substituted indolo 4,3 FG quinolines useful for treating migraine |
KR20120125610A (ko) | 2009-12-30 | 2012-11-16 | 싸이넥시스, 인크. | 시클로스포린 유사체 |
WO2011089166A1 (fr) | 2010-01-19 | 2011-07-28 | Virologik Gmbh | Inhibiteurs du protéasome à base de semicarbazone pour traiter une infection par le vih et une infection par une hépatite |
WO2011094890A1 (fr) | 2010-02-02 | 2011-08-11 | Argusina Inc. | Dérivés phénylalanines et leur utilisation comme modulateurs non peptidiques du récepteur de glp-1 |
UA115523C2 (uk) | 2010-02-05 | 2017-11-27 | Общєство С Огранічєнной Отвєтствєнностью "Новамєдіка" | Тверді форми макроциклічних інгібіторів кінази |
NZ717149A (en) | 2010-02-11 | 2017-06-30 | Celgene Corp | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same for treating various diseases |
DK2542542T3 (en) | 2010-03-02 | 2015-07-20 | Axikin Pharmaceuticals Inc | ISOTOPIC ENRICHED ARYL SULPHONAMIDE CCR3 ANTAGONISTS |
WO2011112689A2 (fr) | 2010-03-11 | 2011-09-15 | Ambit Biosciences Corp. | Sels d'indazolylpyrrolotriazine |
TW201134820A (en) | 2010-03-17 | 2011-10-16 | Axikin Pharmaceuticals Inc | Arylsulfonamide CCR3 antagonists |
WO2011150201A2 (fr) | 2010-05-27 | 2011-12-01 | Ambit Biosciences Corporation | Composés azolylamide et leurs procédés d'utilisation |
WO2011150198A1 (fr) | 2010-05-27 | 2011-12-01 | Ambit Biosciences Corporation | Composés azolyle urée et leurs procédés d'utilisation |
MX2012013879A (es) | 2010-06-01 | 2013-04-03 | Biotheryx Inc | Derivados de hidroxipiridona, composiciones farmceuticas de los mismos y su uso terapeutico para tratar enfermedades proliferativas. |
CN103153309A (zh) | 2010-06-01 | 2013-06-12 | 拜欧赛里克斯公司 | 使用6-环己基-1-羟基-4-甲基-2(1h)-吡啶酮治疗血液恶性肿瘤的方法 |
SG186229A1 (en) | 2010-06-07 | 2013-01-30 | Novomedix Llc | Furanyl compounds and the use thereof |
US20130178522A1 (en) | 2010-07-19 | 2013-07-11 | James M. Jamison | Vitamin c and chromium-free vitamin k, and compositions thereof for treating an nfkb-mediated condition or disease |
US20130225615A1 (en) | 2010-09-01 | 2013-08-29 | Ambit Biosciences Corporation | 2-cycloquinazoline derivatives and methods of use thereof |
US20130303533A1 (en) | 2010-09-01 | 2013-11-14 | Ambit Biosciences Corporation | Azolopyridine and azolopyrimidine compounds and methods of use thereof |
EP2663553B1 (fr) | 2010-09-01 | 2015-08-26 | Ambit Biosciences Corporation | Composés quinoléine et isoquinoléine en tant que modulateurs de jak |
EP2611502A1 (fr) | 2010-09-01 | 2013-07-10 | Ambit Biosciences Corporation | Composés de modulation du récepteur a3 de l'adénosine et leurs méthodes d'utilisation |
US20130225578A1 (en) | 2010-09-01 | 2013-08-29 | Ambit Biosciences Corporation | 7-cyclylquinazoline derivatives and methods of use thereof |
WO2012030894A1 (fr) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | Composés thiénopyridines et thiénopyrimidines et leurs procédés d'utilisation |
AU2011296046B2 (en) | 2010-09-01 | 2015-05-14 | Ambit Biosciences Corporation | Hydrobromide salts of a pyrazolylaminoquinazoline |
WO2012030948A1 (fr) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | Composés de quinazoline et leurs méthodes d'utilisation |
WO2012030914A1 (fr) | 2010-09-01 | 2012-03-08 | Ambit Boisciences Corporation | Dérivés de 4-azolylaminoquinazoline et leurs méthodes d'utilisation |
ES2581840T3 (es) | 2010-09-01 | 2016-09-07 | Ambit Biosciences Corporation | Pirazolilaminoquinazolina ópticamente activa y composiciones farmacéuticas y métodos de uso de la misma |
WO2012044641A1 (fr) | 2010-09-29 | 2012-04-05 | Pathway Therapeutics Inc. | 1,3,5-triazinylbenzimidazolsulfonamides et leur utilisation en thérapie anticancéreuse |
JP2013543512A (ja) | 2010-10-11 | 2013-12-05 | アクシキン ファーマシューティカルズ インコーポレーテッド | アリールスルホンアミドccr3アンタゴニストの塩 |
WO2012064973A2 (fr) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et utilisations de ceux-ci |
WO2012078649A1 (fr) | 2010-12-06 | 2012-06-14 | Follica, Inc. | Procédés destinés à traiter la calvitie et à favoriser la croissance des cheveux |
WO2012080050A1 (fr) | 2010-12-14 | 2012-06-21 | F. Hoffmann-La Roche Ag | Formes solides d'un composé de phénoxybenzènesulfonyle |
US8809349B2 (en) | 2011-01-10 | 2014-08-19 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
CA2825152A1 (fr) | 2011-01-31 | 2012-08-09 | Celgene Corporation | Compositions pharmaceutiques d'analogues de cytidine et leurs methodes d'utilisation |
AR085352A1 (es) | 2011-02-10 | 2013-09-25 | Idenix Pharmaceuticals Inc | Inhibidores macrociclicos de serina proteasa, sus composiciones farmaceuticas y su uso para tratar infecciones por hcv |
CN107375293A (zh) | 2011-03-11 | 2017-11-24 | 细胞基因公司 | 利用3‑(5‑氨基‑2‑甲基‑4‑氧‑4h‑喹唑啉‑3‑基)‑哌啶‑2,6‑二酮治疗癌症的方法 |
WO2012135160A1 (fr) | 2011-03-28 | 2012-10-04 | Pathway Therapeutics Inc. | (aralkylamino et hétéroarylalkylamino alpha-substitués)pyrimidinyl- et 1,3,5-triazinylbenzimidazoles, compositions pharmaceutiques contenant ceux-ci et ces composés pour utilisation dans le traitement de maladies prolifératives |
US20140088103A1 (en) | 2011-03-28 | 2014-03-27 | Mei Pharma, Inc. | (fused ring arylamino and heterocyclylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases |
EP2691389A1 (fr) | 2011-03-28 | 2014-02-05 | MEI Pharma, Inc. | (cycloalkylamino ou hétérocyclylamino alpha-substitué) pyrimidinyl et 1,3,5-triazinyl benzimidazoles, compositions pharmaceutiques les contenant et leur utilisation dans le traitement des maladies prolifératives |
US20120252721A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
JP2014514295A (ja) | 2011-03-31 | 2014-06-19 | アイディニックス ファーマシューティカルズ インコーポレイテッド | ウイルス感染の治療のための化合物および薬学的組成物 |
BR112013033339A2 (pt) | 2011-06-23 | 2016-08-16 | Map Pharmaceuticals Inc | análogos de fluorergolina |
CN103930422A (zh) | 2011-07-19 | 2014-07-16 | 无限药品股份有限公司 | 杂环化合物及其用途 |
JP6027611B2 (ja) | 2011-07-19 | 2016-11-16 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
AU2012302197B2 (en) | 2011-08-29 | 2016-01-07 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
EP2755983B1 (fr) | 2011-09-12 | 2017-03-15 | Idenix Pharmaceuticals LLC. | Composés de carbonyloxyméthylphosphoramidate substitué et compositions pharmaceutiques servant à traiter les infections virales |
JP2014526474A (ja) | 2011-09-12 | 2014-10-06 | アイディニックス ファーマシューティカルズ インコーポレイテッド | ウイルス感染の治療のための化合物および薬学的組成物 |
US9630979B2 (en) | 2011-09-29 | 2017-04-25 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
TWI650321B (zh) | 2011-10-14 | 2019-02-11 | 美商安比特生物科學公司 | 雜環化合物及其使用方法 |
EP2768838A1 (fr) | 2011-10-14 | 2014-08-27 | IDENIX Pharmaceuticals, Inc. | Phosphates 3',5'-cycliques substitués de composés nucléotidiques purines et compositions pharmaceutiques pour le traitement d'infections virales |
WO2013095707A1 (fr) | 2011-12-19 | 2013-06-27 | Map Pharmaceuticals, Inc. | Nouveaux dérivés d'iso-ergoline |
CA2859175A1 (fr) | 2011-12-21 | 2013-06-27 | Map Pharmaceuticals, Inc. | Nouveaux composes neuromodulateurs |
WO2013130600A1 (fr) | 2012-02-29 | 2013-09-06 | Ambit Biosciences Corporation | Formes solides comprenant de la pyrazolylaminoquinazoline optiquement active, compositions à base de celles-ci et leurs utilisations |
EP2852586A1 (fr) | 2012-03-16 | 2015-04-01 | Axikin Pharmaceuticals, Inc. | Inhibiteurs de 3,5-diaminopyrazole kinase |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
SG11201407674TA (en) | 2012-05-22 | 2014-12-30 | Idenix Pharmaceuticals Inc | D-amino acid compounds for liver disease |
WO2013177188A1 (fr) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | Promédicaments de 3',5'-phosphoramidate cyclique pour traiter une infection par le virus de l'hépatite c |
EP2852605B1 (fr) | 2012-05-22 | 2018-01-31 | Idenix Pharmaceuticals LLC | Promédicaments de 3',5'-phosphate cyclique pour traiter une infection par le virus de l'hépatite c |
US9012640B2 (en) | 2012-06-22 | 2015-04-21 | Map Pharmaceuticals, Inc. | Cabergoline derivatives |
SI2882737T1 (sl) | 2012-08-09 | 2019-05-31 | Celgene Corporation | Trdna oblika (S)-3-(4-((4-morfolinometil)benzil)oksi-1-oksoizoindolin-2-il) piperidin-2,6-dion hidroklorida |
RS60416B1 (sr) | 2012-08-09 | 2020-07-31 | Celgene Corp | Lečenje imunoloških i zapaljenskih bolesti |
CA2922849A1 (fr) | 2012-08-31 | 2014-03-06 | Ixchel Pharma, Llc | Agents utiles pour le traitement de l'obesite, du diabete et de troubles associes |
WO2014039748A1 (fr) | 2012-09-07 | 2014-03-13 | Axikin Pharmaceuticals, Inc. | Antagonistes de ccr3 de type arylsulfonamides enrichis en isotopes |
WO2014055647A1 (fr) | 2012-10-03 | 2014-04-10 | Mei Pharma, Inc. | (sulfinyl et sulfonyl benzimidazolyl) pyrimidines et triazines, compositions pharmaceutiques les contenant, et leur utilisation pour traiter les maladies prolifératives |
TR201809048T4 (tr) | 2012-10-08 | 2018-07-23 | Centre Nat Rech Scient | Hcv enfeksiyonu için 2'-kloro nükleosit analogları. |
US20140112886A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
US10723754B2 (en) | 2012-10-22 | 2020-07-28 | Idenix Pharmaceuticals Llc | 2′,4′-bridged nucleosides for HCV infection |
RS58023B2 (sr) | 2012-11-01 | 2021-12-31 | Infinity Pharmaceuticals Inc | Lečenje kancera korišćenjem modulatora izoformi pi3 kinaza |
WO2014074765A2 (fr) | 2012-11-08 | 2014-05-15 | Summa Health System | Vitamine c, vitamine k, un polyphénol et leurs combinaisons pour la cicatrisation des plaies |
EP2920195A1 (fr) | 2012-11-14 | 2015-09-23 | IDENIX Pharmaceuticals, Inc. | Ester de d-alanine d'analogue de rp-nucléoside |
WO2014078436A1 (fr) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | Ester de d-alanine d'analogue de sp-nucléoside |
CA2892227C (fr) | 2012-11-30 | 2020-12-15 | Novomedix, Llc | Sulfonamides biaryliques substitues et leur utilisation |
WO2014099941A1 (fr) | 2012-12-19 | 2014-06-26 | Idenix Pharmaceuticals, Inc. | 4'-fluoro-nucléosides pour le traitement du vhc |
EP2934143A4 (fr) | 2012-12-21 | 2016-06-15 | Map Pharmaceuticals Inc | Nouveaux dérivés de méthysergide |
WO2014110305A1 (fr) | 2013-01-11 | 2014-07-17 | Mayo Foundation For Medical Education And Research | Vitamines c et k pour le traitement de maladies polykystiques |
EP2970358B1 (fr) | 2013-03-04 | 2021-06-30 | Idenix Pharmaceuticals LLC | 3'-désoxynucléosides utilisables en vue du traitement d'une infection par le vhc |
US9339541B2 (en) | 2013-03-04 | 2016-05-17 | Merck Sharp & Dohme Corp. | Thiophosphate nucleosides for the treatment of HCV |
WO2014151386A1 (fr) | 2013-03-15 | 2014-09-25 | Infinity Pharmaceuticals, Inc. | Sels et formes solides d'isoquinolinones et compositions les comprenant et procédés pour les utiliser |
US9187515B2 (en) | 2013-04-01 | 2015-11-17 | Idenix Pharmaceuticals Llc | 2′,4′-fluoro nucleosides for the treatment of HCV |
AU2014273946B2 (en) | 2013-05-30 | 2020-03-12 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using PI3 kinase isoform modulators |
WO2014197578A1 (fr) | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucléosides pour le traitement du virus de l'hépatite c (vhc) |
US20150037282A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
KR20160055170A (ko) | 2013-08-30 | 2016-05-17 | 암비트 바이오사이언시즈 코포레이션 | 바이아릴 아세트아미드 화합물 및 이의 사용 방법 |
NZ631142A (en) | 2013-09-18 | 2016-03-31 | Axikin Pharmaceuticals Inc | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
EP3046924A1 (fr) | 2013-09-20 | 2016-07-27 | IDENIX Pharmaceuticals, Inc. | Inhibiteurs du virus de l'hépatite c |
US9700549B2 (en) | 2013-10-03 | 2017-07-11 | David Wise | Compositions and methods for treating pelvic pain and other conditions |
JP6466924B2 (ja) | 2013-10-04 | 2019-02-06 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US20160244452A1 (en) | 2013-10-21 | 2016-08-25 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
WO2015061683A1 (fr) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | Pronucléotides thiophosphoramidates à acide aminé d et pronucléotides thiophosphoramidates à d-analine de composés de nucléoside utiles pour le traitement du vhc |
US20160271162A1 (en) | 2013-11-01 | 2016-09-22 | Idenix Pharmacueticals, Llc | D-alanine phosphoramide pronucleotides of 2'-methyl 2'-fluro guanosine nucleoside compounds for the treatment of hcv |
AU2014354775A1 (en) | 2013-11-27 | 2016-05-19 | Idenix Pharmaceuticals Llc | Nucleotides for the treatment of liver cancer |
US20170198005A1 (en) | 2013-11-27 | 2017-07-13 | Idenix Pharmaceuticals Llc | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
WO2015095419A1 (fr) | 2013-12-18 | 2015-06-25 | Idenix Pharmaceuticals, Inc. | Nucléosides 4'-or pour le traitement du vhc |
CN103746201B (zh) * | 2013-12-18 | 2016-04-20 | 宁波意欧迅网络通信有限公司 | 高频数据插头和电子配线线缆 |
WO2015134560A1 (fr) | 2014-03-05 | 2015-09-11 | Idenix Pharmaceuticals, Inc. | Formes solides d'un composé inhibiteur des virus de la famille des flaviviridae et sels de celui-ci |
DK3119397T3 (da) | 2014-03-19 | 2022-03-28 | Infinity Pharmaceuticals Inc | Heterocykliske forbindelser til anvendelse i behandling af PI3K-gamma-medierede lidelser |
US10202398B2 (en) | 2014-03-20 | 2019-02-12 | Capella Therapeutics, Inc. | Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer |
MX2016012097A (es) | 2014-03-20 | 2017-04-27 | Capella Therapeutics Inc | Derivados de bencimidazol como inhibidores de tirosina cinasa erbb para el tratamiento del cáncer. |
AU2015243437B2 (en) | 2014-04-09 | 2019-08-29 | Siteone Therapeutics, Inc. | 10',11'-modified saxitoxins useful for the treatment of pain |
EP3131914B1 (fr) | 2014-04-16 | 2023-05-10 | Idenix Pharmaceuticals LLC | Nucléosides méthyle ou alcynyle substitués en position 3 pour le traitement du virus de l'hépatite c |
WO2015168079A1 (fr) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Dérivés de pyrimidine ou de pyridine utiles en tant qu'inhibiteurs de pi3k |
EP3444011A1 (fr) | 2014-05-12 | 2019-02-20 | Conatus Pharmaceuticals, Inc. | Traitement des complications de maladies de foie chroniques avec emricasan |
CA2947939A1 (fr) | 2014-05-28 | 2015-12-03 | Idenix Pharmaceuticals Llc | Derives de nucleosides pour le traitement du cancer |
US9527815B2 (en) | 2014-06-18 | 2016-12-27 | Biotheryx, Inc. | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases |
EA034691B1 (ru) | 2014-06-19 | 2020-03-06 | Ариад Фармасьютикалз, Инк. | Гетероарильные соединения для ингибирования киназ |
US9499514B2 (en) | 2014-07-11 | 2016-11-22 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
US20170319548A1 (en) | 2014-09-12 | 2017-11-09 | Tobira Therapeutics, Inc. | Cenicriviroc combination therapy for the treatment of fibrosis |
WO2016054491A1 (fr) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et leurs utilisations |
KR20210142781A (ko) | 2014-10-21 | 2021-11-25 | 다케다 야쿠힌 고교 가부시키가이샤 | 결정 형태의 5-클로로-n4-[2-(디메틸포스포릴)페닐]-n2-{2-메톡시-4-[4-(4-메틸피페라진-1-일)피페리딘-1-일]피리미딘-2,4-디아민 |
US20170354639A1 (en) | 2014-10-24 | 2017-12-14 | Biogen Ma Inc. | Diterpenoid derivatives and methods of use thereof |
MY191736A (en) | 2014-12-23 | 2022-07-13 | Axikin Pharmaceuticals Inc | 3,5-diaminopyrazole kinase inhibitors |
CN107428745A (zh) | 2015-01-20 | 2017-12-01 | Xoc制药股份有限公司 | 麦角灵化合物及其用途 |
EP3247357A4 (fr) | 2015-01-20 | 2018-07-11 | Xoc Pharmaceuticals, Inc | Composés d'isoergoline et leurs utilisations |
CN108368147A (zh) | 2015-05-27 | 2018-08-03 | 南方研究院 | 用于治疗癌症的核苷酸 |
US20190015396A1 (en) | 2015-06-23 | 2019-01-17 | Neurocrine Biosciences, Inc. | Vmat2 inhibitors for treating neurological diseases or disorders |
DK3277842T5 (da) | 2015-08-17 | 2020-08-31 | Kura Oncology Inc | Fremgangsmåder til at behandle kræftpatienter med farnesyl-transferase-inhibitorer |
CN108473503A (zh) | 2015-09-30 | 2018-08-31 | 赛特温治疗公司 | 用于治疗疼痛的11,13-修饰的石房蛤毒素类化合物 |
PT3368534T (pt) | 2015-10-30 | 2021-03-09 | Neurocrine Biosciences Inc | Ditosilato de valbenazina e polimorfos do mesmo |
WO2017079566A1 (fr) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Inhibiteurs de caspase destinés à être utilisés dans le traitement du cancer |
US10112924B2 (en) | 2015-12-02 | 2018-10-30 | Astraea Therapeutics, Inc. | Piperdinyl nociceptin receptor compounds |
PT3394057T (pt) | 2015-12-23 | 2022-04-21 | Neurocrine Biosciences Inc | Método sintético para a preparação de 2-amino-3-metilbutanoato de di(4-metilbenzenesulfonato) (s)-(2r,3r,11br)-3-isobutil-9,10-dimetoxi-2,3,4,6,7,11bhexaidro-1h-pirido[2,1,-a]lsoquinolin-2-ilo |
SG11201805480TA (en) | 2015-12-31 | 2018-07-30 | Conatus Pharmaceuticals Inc | Methods of using caspase inhibitors in treatment of liver disease |
EP3808346B1 (fr) | 2016-01-08 | 2023-07-19 | Celgene Corporation | Composés antiprolifératifs pour utilisation dans le traitement de la leucémie |
US10189808B2 (en) | 2016-01-08 | 2019-01-29 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
JP6880037B2 (ja) | 2016-01-08 | 2021-06-02 | セルジーン コーポレイション | がんの治療方法と、治療法に対する臨床的感度の予測因子としてのバイオマーカーの使用 |
WO2017161116A1 (fr) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues de composés isoquinolinone et quinazolinone et leurs utilisations comme inhibiteurs de la kinase pi3k |
AU2017250086A1 (en) | 2016-04-11 | 2018-09-20 | Clexio Biosciences Ltd. | Deuterated ketamine derivatives |
US10047077B2 (en) | 2016-04-13 | 2018-08-14 | Skyline Antiinfectives, Inc. | Deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams |
US20190119758A1 (en) | 2016-04-22 | 2019-04-25 | Kura Oncology, Inc. | Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors |
ES2912921T3 (es) | 2016-04-29 | 2022-05-30 | Fgh Biotech Inc | Compuestos de pirazol disustituidos para el tratamiento de enfermedades |
TWI753910B (zh) | 2016-05-16 | 2022-02-01 | 美商拜歐斯瑞克斯公司 | 吡啶硫酮、其醫藥組合物及其治療增生性、炎性、神經退化性或免疫介導疾病之治療用途 |
US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AU2017323521B9 (en) | 2016-09-07 | 2022-02-17 | Fgh Biotech, Inc. | Di-substituted pyrazole compounds for the treatment of diseases |
AU2017326558B2 (en) | 2016-09-19 | 2022-01-06 | Mei Pharma, Inc. | Combination therapy |
KR20190082247A (ko) | 2016-11-03 | 2019-07-09 | 쿠라 온콜로지, 인크. | 파르네실전달효소 억제제를 이용하여 암 환자를 치료하는 방법 |
WO2018089692A1 (fr) | 2016-11-09 | 2018-05-17 | Phloronol, Inc. | Dérivés d'eckol, procédés de synthèse et utilisations associées |
CA3042055A1 (fr) | 2016-11-09 | 2018-05-17 | Novomedix, Llc | Sels de nitrite de 1,1-dimethylbiguanide, compositions pharmaceutiques et methodes d'utilisation |
EP3548007A4 (fr) | 2016-12-01 | 2020-08-12 | Ignyta, Inc. | Méthodes de traitement du cancer |
US20200078352A1 (en) | 2016-12-02 | 2020-03-12 | Neurocrine Biosciences, Inc. | Use of Valbenazine for Treating Schizophrenia or Schizoaffective Disorder |
SG11201906883SA (en) | 2017-01-27 | 2019-08-27 | Neurocrine Biosciences Inc | Methods for the administration of certain vmat2 inhibitors |
KR102003179B1 (ko) | 2017-02-21 | 2019-07-23 | 쿠라 온콜로지, 인크. | 파르네실트랜스퍼라제 억제제를 사용하는 암 환자의 치료 방법 |
US10137121B2 (en) | 2017-02-21 | 2018-11-27 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
WO2018164996A1 (fr) | 2017-03-06 | 2018-09-13 | Neurocrine Biosciences, Inc. | Posologie pour la valbénazine |
US11555031B2 (en) | 2017-03-20 | 2023-01-17 | The Broad Institute, Inc. | Compounds and methods for regulating insulin secretion |
CN110799192A (zh) | 2017-03-27 | 2020-02-14 | 加利福尼亚大学董事会 | 治疗癌症的组合物和方法 |
KR20200012833A (ko) | 2017-03-29 | 2020-02-05 | 사이트원 테라퓨틱스, 인코포레이티드 | 통증 치료용 11,13-개질된 색시톡신 |
CN110914276A (zh) | 2017-03-29 | 2020-03-24 | 赛特温治疗公司 | 用于治疗疼痛的11,13-修饰的石房蛤毒素类化合物 |
WO2018200605A1 (fr) | 2017-04-26 | 2018-11-01 | Neurocrine Biosciences, Inc. | Utilisation de valbénazine pour le traitement de la dyskinésie induite par la lévodopa |
JOP20190219A1 (ar) | 2017-05-09 | 2019-09-22 | Cardix Therapeutics LLC | تركيبات صيدلانية وطرق لعلاج أمراض القلب والأوعية الدموية |
US10085999B1 (en) | 2017-05-10 | 2018-10-02 | Arixa Pharmaceuticals, Inc. | Beta-lactamase inhibitors and uses thereof |
JP7212956B2 (ja) | 2017-05-19 | 2023-01-26 | エヌフレクション セラピューティクス インコーポレイテッド | 皮膚障害の処置用のピロロピリジン-アニリン化合物 |
MX2019013562A (es) | 2017-05-19 | 2020-08-03 | Nflection Therapeutics Inc | Compuestos de anilina heteroaromatica o fusionados para el tratamiento de trastornos dermicos. |
BR112019025420A2 (pt) | 2017-06-01 | 2020-06-16 | Xoc Pharmaceuticals, Inc. | Compostos policíclicos e usos destes |
JP7325400B2 (ja) | 2017-08-07 | 2023-08-14 | クラ オンコロジー, インコーポレイテッド | ファルネシルトランスフェラーゼ阻害剤を用いてがんを治療する方法 |
US10806730B2 (en) | 2017-08-07 | 2020-10-20 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
WO2019060322A2 (fr) | 2017-09-21 | 2019-03-28 | Neurocrine Biosciences, Inc. | Formulation de valbenazine à dosage élevé et compositions, procédés et kits associés |
WO2019071021A2 (fr) | 2017-10-04 | 2019-04-11 | The Regents Of The University Of California | Oligosaccharides immunomodulateurs |
CN116492340A (zh) | 2017-10-10 | 2023-07-28 | 纽罗克里生物科学有限公司 | 施用某些vmat2抑制剂的方法 |
US10993941B2 (en) | 2017-10-10 | 2021-05-04 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
WO2019113269A1 (fr) | 2017-12-08 | 2019-06-13 | Kura Oncology, Inc. | Méthodes de traitement de patients cancéreux avec des inhibiteurs de la farnésyltransférase |
US11701334B2 (en) | 2018-01-10 | 2023-07-18 | Cura Therapeutics, Llc | Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications |
WO2019139871A1 (fr) | 2018-01-10 | 2019-07-18 | Cura Therapeutics Llc | Compositions pharmaceutiques comprenant des acides dicarboxyliques et leurs applications thérapeutiques |
BR112020024018A2 (pt) | 2018-06-14 | 2021-02-23 | Neurocrine Biosciences Inc. | compostos inibidores de vmat2, composições e métodos relacionados a eles |
CA3105352A1 (fr) | 2018-06-29 | 2020-01-02 | Histogen, Inc. | Derives d'acide (s)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoique et composes apparentes utilises en tant qu'inhibiteurs de caspase pour le traitement de maladies cardiovasculaires |
KR20210044817A (ko) | 2018-08-15 | 2021-04-23 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 특정 vmat2 억제제의 투여 방법 |
US20220009938A1 (en) | 2018-10-03 | 2022-01-13 | Siteone Therapeutics, Inc. | 11,13-modified saxitoxins for the treatment of pain |
CN113286591A (zh) | 2018-11-01 | 2021-08-20 | 库拉肿瘤学公司 | 用法尼基转移酶抑制剂治疗癌症的方法 |
AU2019383311A1 (en) | 2018-11-20 | 2021-06-10 | Nflection Therapeutics, Inc. | Cyanoaryl-aniline compounds for treatment of dermal disorders |
EP4233865A3 (fr) | 2018-11-20 | 2023-09-27 | NFlection Therapeutics, Inc. | Composés aryl-aniline et hétéroaryl-aniline pour le traitement de cancers de la peau |
EP3883567A4 (fr) | 2018-11-20 | 2022-07-27 | NFlection Therapeutics, Inc. | Composés naphthyridinone-aniline destinés au traitement d'affections de la peau |
CA3120336A1 (fr) | 2018-11-20 | 2020-05-28 | Nflection Therapeutics, Inc. | Composes d'aryl-aniline et d'heteroaryl-aniline pour le traitement de marques de naissance |
EP3898609A1 (fr) | 2018-12-19 | 2021-10-27 | Shy Therapeutics LLC | Composés interagissant avec la superfamille ras pour le traitement de cancers, de maladies inflammatoires, de rasopathies et de maladie fibrotique |
WO2020132700A1 (fr) | 2018-12-21 | 2020-06-25 | Fgh Biotech Inc. | Procédés d'utilisation d'inhibiteurs de srebp en combinaison avec du niclosamide et des analogues de celui-ci |
JP2022514654A (ja) | 2018-12-21 | 2022-02-14 | クラ オンコロジー, インコーポレイテッド | 扁平上皮癌のための治療法 |
WO2020163554A1 (fr) | 2019-02-06 | 2020-08-13 | Dice Alpha, Inc. | Modulateurs d'il-17a et leurs utilisations |
US20220142983A1 (en) | 2019-03-01 | 2022-05-12 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
US11597703B2 (en) | 2019-03-07 | 2023-03-07 | Histogen, Inc. | Caspase inhibitors and methods of use thereof |
TW202108170A (zh) | 2019-03-15 | 2021-03-01 | 美商庫拉腫瘤技術股份有限公司 | 以法呢基轉移酶(farnesyltransferase)抑制劑治療癌症患者之方法 |
KR20210144778A (ko) | 2019-03-29 | 2021-11-30 | 쿠라 온콜로지, 인크. | 파르네실트랜스퍼라제 억제제를 사용한 편평 세포 암종의 치료 방법 |
US20220168296A1 (en) | 2019-04-01 | 2022-06-02 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
US20220305001A1 (en) | 2019-05-02 | 2022-09-29 | Kura Oncology, Inc. | Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors |
AU2020311404A1 (en) | 2019-07-11 | 2022-03-03 | Cura Therapeutics, Llc | Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications for the treatment of neurodegenerative diseases |
CA3146159A1 (fr) | 2019-07-11 | 2021-01-14 | Cura Therapeutics, Llc | Composes de phenyle et compositions pharmaceutiques associees, et leurs applications therapeutiques |
US11098002B2 (en) | 2019-07-26 | 2021-08-24 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease |
US10940141B1 (en) | 2019-08-23 | 2021-03-09 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
BR112022004802A2 (pt) | 2019-09-16 | 2022-08-23 | Dice Alpha Inc | Moduladores de il-17a e usos dos mesmos |
EP4034236A1 (fr) | 2019-09-26 | 2022-08-03 | Abionyx Pharma SA | Composés utiles pour le traitement des maladies du foie |
EP4037687A4 (fr) | 2019-10-01 | 2023-09-27 | Molecular Skin Therapeutics, Inc. | Composés de benzoxazinone utilisés comme inhibiteurs doubles de klk5/7 |
US11529331B2 (en) | 2020-05-29 | 2022-12-20 | Boulder Bioscience Llc | Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane |
WO2021257828A1 (fr) | 2020-06-18 | 2021-12-23 | Shy Therapeutics, Llc | Thiénopyrimidines qui interagissent avec la superfamille ras pour le traitement de cancers, de maladies inflammatoires, de rasopathies et d'une maladie fibreuse |
US12024521B2 (en) | 2020-06-30 | 2024-07-02 | Prosetta Biosciences, Inc. | Isoquinoline derivatives, methods of synthesis and uses thereof |
EP4196482A1 (fr) | 2020-08-14 | 2023-06-21 | SiteOne Therapeutics, Inc. | Inhibiteurs de cétone non hydratés de nav1.7 pour le traitement de la douleur |
WO2022165000A1 (fr) | 2021-01-27 | 2022-08-04 | Shy Therapeutics, Llc | Méthodes pour le traitement d'une maladie fibrotique |
EP4284377A1 (fr) | 2021-01-27 | 2023-12-06 | Shy Therapeutics LLC | Méthodes pour le traitement d'une maladie fibrotique |
WO2022189856A1 (fr) | 2021-03-08 | 2022-09-15 | Abionyx Pharma Sa | Composés utiles pour le traitement des maladies du foie |
IL305752A (en) | 2021-03-10 | 2023-11-01 | Dice Molecules Sv Inc | INTEGRIN INHIBITORS OF ALPHA V BETA 6 AND ALPHA V BETA 1 AND THEIR USES |
EP4326721A1 (fr) | 2021-04-22 | 2024-02-28 | Protego Biopharma, Inc. | Imidazolidinediones et imidazolidinones spirocycliques pour le traitement d'une amylose à chaîne légère |
EP4347568A1 (fr) | 2021-05-27 | 2024-04-10 | Protego Biopharma, Inc. | Hétéroaryl-diamides activateurs d'ire1/xbp1s |
US12017997B2 (en) | 2021-10-22 | 2024-06-25 | Prosetta Biosciences, Inc. | Host-targeted pan-respiratory antiviral small molecule therapeutics |
TW202327590A (zh) | 2021-11-30 | 2023-07-16 | 美商庫拉腫瘤技術股份有限公司 | 大環化合物及組合物以及其製備及使用方法 |
WO2023129577A1 (fr) | 2022-01-03 | 2023-07-06 | Lilac Therapeutics, Inc. | Promédicaments à base de thiol cyclique |
WO2023129576A2 (fr) | 2022-01-03 | 2023-07-06 | Lilac Therapeutics, Inc. | Promedicaments thiol acycliques |
US20230303580A1 (en) | 2022-03-28 | 2023-09-28 | Isosterix, Inc. | Inhibitors of the myst family of lysine acetyl transferases |
TW202342070A (zh) | 2022-03-30 | 2023-11-01 | 美商拜奧馬林製藥公司 | 肌萎縮蛋白外顯子跳躍寡核苷酸 |
GB2619907A (en) | 2022-04-01 | 2023-12-27 | Kanna Health Ltd | Novel crystalline salt forms of mesembrine |
US20230331693A1 (en) | 2022-04-14 | 2023-10-19 | Bristol-Myers Squibb Company | Gspt1 compounds and methods of use of the novel compounds |
WO2023201348A1 (fr) | 2022-04-15 | 2023-10-19 | Celgene Corporation | Procédés de prédiction de la réactivité d'un lymphome à un médicament et méthodes de traitement du lymphome |
WO2023211990A1 (fr) | 2022-04-25 | 2023-11-02 | Siteone Therapeutics, Inc. | Inhibiteurs d'amides hétérocycliques bicycliques de na v1.8 pour le traitement de la douleur |
US20230416741A1 (en) | 2022-05-05 | 2023-12-28 | Biomarin Pharmaceutical Inc. | Method of treating duchenne muscular dystrophy |
US20240158370A1 (en) | 2022-09-09 | 2024-05-16 | Innovo Therapeutics, Inc. | CK1 alpha AND DUAL CK1 alpha / GSPT1 DEGRADING COMPOUNDS |
US20240131005A1 (en) | 2022-09-30 | 2024-04-25 | Boulder Bioscience Llc | Compositions and methods for treating non-hemorrhagic closed head injury |
WO2024086246A2 (fr) | 2022-10-18 | 2024-04-25 | Eluciderm Inc. | 3,4 a, 5, 7, 8, 8 a-hexahydro-4h-thiop yrano [4,3-djpyrimidin-4-ones substituées en position 2 pour le traitement des plaies |
US20240174672A1 (en) | 2022-10-26 | 2024-05-30 | Protego Biopharma, Inc. | Spirocycle Containing Pyridone Compounds |
US20240174673A1 (en) | 2022-10-26 | 2024-05-30 | Protego Biopharma, Inc. | Spirocycle Containing Pyridine Compounds |
WO2024092040A1 (fr) | 2022-10-26 | 2024-05-02 | Protego Biopharma, Inc. | Composés hétéroaryle bicycliques contenant un spirocycle |
WO2024118810A1 (fr) | 2022-11-30 | 2024-06-06 | Protego Biopharma, Inc. | Activateurs de ire1/xbp1 diamide de pyrazole cyclique |
WO2024118801A1 (fr) | 2022-11-30 | 2024-06-06 | Protego Biopharma, Inc. | Diamides hétéroaryles linéaires comme activateurs d'ire1/xbp1s |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2491537A (en) * | 1947-06-03 | 1949-12-20 | Welch Henry | Liquid injectable oil-pectin-drug therapeutic compositions |
US2807569A (en) * | 1953-01-17 | 1957-09-24 | Organon | Adrenocorticotropic hormone composition |
GB807692A (en) * | 1957-05-07 | 1959-01-21 | Lilly Co Eli | Corticotropin reaction complexes |
US2964448A (en) * | 1959-01-27 | 1960-12-13 | Anschel Joachim | Relaxin composition and process for preparing same |
US3118815A (en) * | 1959-09-28 | 1964-01-21 | Upjohn Co | Growth hormone and recovery thereof |
NL289055A (fr) * | 1963-02-15 | |||
US3810881A (en) * | 1971-06-18 | 1974-05-14 | Ciba Geigy Corp | Peptides having d-alpha-phenylglycine,l-lysine and l-ornithine in positions 1,17 and 18,respectively |
BE795516A (fr) * | 1972-02-17 | 1973-08-16 | Ciba Geigy | Preparations de peptides huileuses et injectables et procede pour leur preparation |
GB1454105A (en) * | 1972-11-04 | 1976-10-27 | Hoechst Ag | Preparation containing luteinizing hormone-releasing factor |
US4172138A (en) * | 1977-03-23 | 1979-10-23 | Rhodes Russell E | Method and composition of matter for the treatment of dry cows for mastitis |
US4256737A (en) * | 1979-06-11 | 1981-03-17 | Syntex (U.S.A.) Inc. | Long acting depot injectable formulations for LH-RH analogues |
US4328214A (en) * | 1979-07-04 | 1982-05-04 | Ciba-Geigy Corporation | Cyclopeptides and pharmaceutical preparations thereof and also processes for their manufacture |
CA1146866A (fr) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Procede de production d'un compose pharmaceutique a liberation continue sous forme solide |
EP0092918B1 (fr) * | 1982-04-22 | 1988-10-19 | Imperial Chemical Industries Plc | Formulations à libération continue |
US4659696A (en) * | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
US4452775A (en) * | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
KR890002631B1 (ko) * | 1984-10-04 | 1989-07-21 | 몬산토 캄파니 | 생물학적으로 활성인 소마토트로핀을 지속적으로 유리하는 조성물 |
US5474980A (en) * | 1984-10-04 | 1995-12-12 | Monsanto Company | Prolonged release of biologically active somatotropins |
EP0177342A3 (fr) * | 1984-10-04 | 1987-12-02 | Genentech, Inc. | Formulations orales de protéines thérapeutiques |
US5086041A (en) * | 1984-10-04 | 1992-02-04 | Monsanto Company | Methods of using prolonged release somatotropin compositions |
US5411951A (en) * | 1984-10-04 | 1995-05-02 | Monsanto Company | Prolonged release of biologically active somatotropin |
-
1985
- 1985-10-02 KR KR1019850007270A patent/KR890002631B1/ko not_active IP Right Cessation
- 1985-10-02 ES ES547489A patent/ES8702440A1/es not_active Expired
- 1985-10-02 HU HU854931A patent/HU196714B/hu not_active IP Right Cessation
- 1985-10-03 CA CA000490016A patent/CA1309018C/fr not_active Expired - Lifetime
- 1985-10-03 NZ NZ213701A patent/NZ213701A/xx unknown
- 1985-10-03 PT PT81248A patent/PT81248B/pt unknown
- 1985-10-03 AT AT89113657T patent/ATE132372T1/de not_active IP Right Cessation
- 1985-10-03 AU AU48237/85A patent/AU573904B2/en not_active Ceased
- 1985-10-03 CZ CS878156A patent/CZ284472B6/cs not_active IP Right Cessation
- 1985-10-03 PL PL1985261273A patent/PL261273A1/xx unknown
- 1985-10-03 IE IE242285A patent/IE65392B1/en not_active IP Right Cessation
- 1985-10-03 DK DK449585A patent/DK449585A/da not_active Application Discontinuation
- 1985-10-03 DD DD85281414A patent/DD244914A5/de not_active IP Right Cessation
- 1985-10-03 CN CN85109638A patent/CN1007124B/zh not_active Expired
- 1985-10-03 GR GR852398A patent/GR852398B/el unknown
- 1985-10-03 SU SU853963358A patent/SU1595330A3/ru active
- 1985-10-03 DE DE8585870135T patent/DE3582548D1/de not_active Expired - Fee Related
- 1985-10-03 BG BG71902A patent/BG47039A3/xx unknown
- 1985-10-03 NO NO853909A patent/NO173975C/no not_active IP Right Cessation
- 1985-10-03 JP JP60221112A patent/JPH0745409B2/ja not_active Expired - Fee Related
- 1985-10-03 PL PL1985255622A patent/PL152711B1/pl unknown
- 1985-10-03 IL IL76554A patent/IL76554A/xx not_active IP Right Cessation
- 1985-10-03 EP EP85870135A patent/EP0177478B2/fr not_active Expired - Lifetime
- 1985-10-03 DE DE3588074T patent/DE3588074D1/de not_active Expired - Lifetime
- 1985-10-03 CS CS711885A patent/CS274717B2/cs not_active IP Right Cessation
- 1985-10-03 ZA ZA857642A patent/ZA857642B/xx unknown
- 1985-10-03 UA UA3963358A patent/UA8352A1/uk unknown
- 1985-10-04 YU YU1584/85A patent/YU45281B/xx unknown
-
1988
- 1988-07-14 PT PT81248A patent/PT81248B1/pt not_active IP Right Cessation
-
1989
- 1989-08-12 CN CN89106684A patent/CN1031038C/zh not_active Expired - Lifetime
- 1989-09-29 US US07/414,503 patent/US5013713A/en not_active Expired - Lifetime
-
1993
- 1993-07-14 GE GEAP19931022A patent/GEP19960332B/en unknown
-
1995
- 1995-12-11 US US08/570,304 patent/US5739108A/en not_active Expired - Fee Related
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0177478B2 (fr) | Libération prolongée de somatotropines biologiquement actifs | |
US5411951A (en) | Prolonged release of biologically active somatotropin | |
US4985404A (en) | Prolonged release of biologically active polypeptides | |
US7037516B2 (en) | Non-aqueous surfactant-containing formulations for extended release of somatotropin | |
US5595971A (en) | Prolonged release of biologically active polypeptides | |
US5086041A (en) | Methods of using prolonged release somatotropin compositions | |
JPH04211018A (ja) | 生物学的活性を有するポリペプチドを持続的に放出する組成物 | |
EP0343696B1 (fr) | Zinc-somatotropines | |
US7030091B2 (en) | Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin | |
KR100890679B1 (ko) | 소마토트로핀의 지속적인 방출을 위한 비수성 주사제제들 | |
NO314387B1 (no) | Sinkbundet somatotropinkompleks og i det vesentlige ikke- vandig somatropinpreparat med langvarige frigivelseskarakteristika for parenteraladministrering til et dyr for vekst- og produktivitetsökning |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
PUAL | Search report despatched |
Free format text: ORIGINAL CODE: 0009013 |
|
AK | Designated contracting states |
Kind code of ref document: A3 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
17P | Request for examination filed |
Effective date: 19870820 |
|
17Q | First examination report despatched |
Effective date: 19890125 |
|
EL | Fr: translation of claims filed | ||
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
REF | Corresponds to: |
Ref document number: 62598 Country of ref document: AT Date of ref document: 19910515 Kind code of ref document: T |
|
XX | Miscellaneous (additional remarks) |
Free format text: TEILANMELDUNG 89113657.4 EINGEREICHT AM 03/10/85. |
|
ET | Fr: translation filed | ||
REF | Corresponds to: |
Ref document number: 3582548 Country of ref document: DE Date of ref document: 19910523 |
|
ITF | It: translation for a ep patent filed |
Owner name: MODIANO & ASSOCIATI S.R.L. |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: CL |
|
PLBI | Opposition filed |
Free format text: ORIGINAL CODE: 0009260 |
|
26 | Opposition filed |
Opponent name: ELI LILLY AND COMPANY Effective date: 19911111 |
|
PLBI | Opposition filed |
Free format text: ORIGINAL CODE: 0009260 |
|
NLR1 | Nl: opposition has been filed with the epo |
Opponent name: ELI LILLY AND COMPANY. |
|
26 | Opposition filed |
Opponent name: THE UPJOHN COMPANY Effective date: 19920113 Opponent name: ELI LILLY AND COMPANY Effective date: 19911111 |
|
NLR1 | Nl: opposition has been filed with the epo |
Opponent name: THE UPJOHN COMPANY. |
|
EPTA | Lu: last paid annual fee | ||
EAL | Se: european patent in force in sweden |
Ref document number: 85870135.2 |
|
NLT2 | Nl: modifications (of names), taken from the european patent patent bulletin |
Owner name: MONSANTO COMPANY |
|
PLAW | Interlocutory decision in opposition |
Free format text: ORIGINAL CODE: EPIDOS IDOP |
|
APAC | Appeal dossier modified |
Free format text: ORIGINAL CODE: EPIDOS NOAPO |
|
APAC | Appeal dossier modified |
Free format text: ORIGINAL CODE: EPIDOS NOAPO |
|
PUAH | Patent maintained in amended form |
Free format text: ORIGINAL CODE: 0009272 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: PATENT MAINTAINED AS AMENDED |
|
27A | Patent maintained in amended form |
Effective date: 19970305 |
|
AK | Designated contracting states |
Kind code of ref document: B2 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
ET3 | Fr: translation filed ** decision concerning opposition | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: AEN Free format text: MAINTIEN DU BREVET DONT L'ETENDUE A ETE MODIFIEE |
|
ITF | It: translation for a ep patent filed |
Owner name: 0414;04MIFMODIANO & ASSOCIATI S.R.L. |
|
NLR2 | Nl: decision of opposition | ||
NLR3 | Nl: receipt of modified translations in the netherlands language after an opposition procedure | ||
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20010920 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20010925 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20011004 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20011010 Year of fee payment: 17 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20021003 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20021031 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: PHARMACIA CORPORATION TRANSFER- MONSANTO TECHNOLOG Ref country code: CH Ref legal event code: PFA Free format text: MONSANTO COMPANY TRANSFER- PHARMACIA CORPORATION |
|
BERE | Be: lapsed |
Owner name: *MONSANTO CY Effective date: 20021031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20030501 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20030501 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20030501 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20030924 Year of fee payment: 19 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20031020 Year of fee payment: 19 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20031021 Year of fee payment: 19 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20031022 Year of fee payment: 19 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: AT Payment date: 20040921 Year of fee payment: 20 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041003 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041004 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041031 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041031 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20041003 |
|
EUG | Se: european patent has lapsed | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20050630 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
APAH | Appeal reference modified |
Free format text: ORIGINAL CODE: EPIDOSCREFNO |